Non-invasive magnetic or electrical nerve stimulation to treat or prevent dementia

ABSTRACT

Devices, systems and methods are disclosed for treating or preventing dementia, such as Alzheimer&#39;s disease. The methods comprise transmitting impulses of energy non-invasively to selected nerve fibers, particularly those in a vagus nerve, that modulate the activity of a patient&#39;s locus ceruleus. The transmitted energy impulses, comprising magnetic and/or electrical energy, stimulate the selected nerve fibers to cause the locus ceruleus to release norepinephrine into regions of the brain that contain beta-amyloids. The norepinephrine counteracts neuroinflammation that would damage neurons in those regions and the locus ceruleus, thereby arresting or slowing the progression of the disease in the patient.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/671,859 filed Nov. 8, 2012; which is a continuation-in-part of U.S.patent application Ser. No. 13/183,765 filed Jul. 15, 2011, now U.S.Pat. No. 8,874,227 issued Oct. 28, 2014, (i) which claims the benefit ofU.S. Provisional Patent Application No. 61/488,208 filed May 20, 2011,and (ii) which is a continuation-in-part of U.S. patent application Ser.No. 13/183,721 filed Jul. 15, 2011, now U.S. Pat. No. 8,676,324 issuedMar. 18, 2014, (a) which claims the benefit of U.S. Provisional PatentApplication No. 61/487,439 filed May 18, 2011, and (b) which is acontinuation-in-part of U.S. patent application Ser. No. 13/109,250filed May 17, 2011, now U.S. Pat. No. 8,676,330 issued Mar. 18, 2014,(1) which claims the benefit of U.S. Provisional Patent Application No.61/471,405 filed Apr. 4, 2011, and (2) which is a continuation-in-partof U.S. patent application Ser. No. 13/075,746 filed Mar. 30, 2011, nowU.S. Pat. No. 8,874,205 issued Oct. 28, 2014, (x) which claims thebenefit of U.S. provisional patent application 61/451,259 filed Mar. 10,2011, and (y) which is a continuation-in-part of U.S. patent applicationSer. No. 13/024,727 filed Feb. 10, 2011, now U.S. Pat. No. 9,089,719issued Jul. 28, 2015; which is a continuation-in-part of U.S. patentapplication Ser. No. 13/005,005 filed Jan. 12, 2011, now U.S. Pat. No.8,868,177 issued Oct. 21, 2014; which is a continuation-in-part of U.S.patent application Ser. No. 12/964,050 filed Dec. 9, 2010, nowabandoned, (I) which claims the benefit of U.S. Provisional PatentApplication No. 61/415,469 filed Nov. 19, 2010, and (II) which is acontinuation-in-part of U.S. patent application Ser. No. 12/859,568filed Aug. 19, 2010, now U.S. Pat. No. 9,037,247 issued May 19, 2015;which is a (A) continuation-in-part application of U.S. patentapplication Ser. No. 12/612,177 filed Nov. 4, 2009, now U.S. Pat. No.8,041,428 issued Oct. 18, 2011, and is a (B) continuation-in-part ofU.S. patent application Ser. No. 12/408,131 filed Mar. 20, 2009, nowU.S. Pat. No. 8,812,112 issued Aug. 19, 2014; each of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Theinvention relates more specifically to devices and methods for treatingconditions associated with dementia, particularly Alzheimer's disease.The energy impulses (and/or fields) that are used to treat thoseconditions comprise electrical and/or electromagnetic energy, deliverednon-invasively to the patient.

The use of electrical stimulation for treatment of medical conditions iswell known. For example, electrical stimulation of the brain withimplanted electrodes has been approved for use in the treatment ofvarious conditions, including pain and movement disorders such asessential tremor and Parkinson's disease.

Another application of electrical stimulation of nerves is the treatmentof radiating pain in the lower extremities by stimulating the sacralnerve roots at the bottom of the spinal cord [Paul F. WHITE, Shitong Liand Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic PainManagement. Anesth Analg 92(2001):505-513; U.S. Pat. No. 6,871,099entitled Fully implantable microstimulator for spinal cord stimulationas a therapy for chronic pain, to Whitehurst, et al].

The form of electrical stimulation that is most relevant to the presentinvention is vagus nerve stimulation (VNS, also known as vagal nervestimulation). It was developed initially for the treatment of partialonset epilepsy and was subsequently developed for the treatment ofdepression and other disorders. The left vagus nerve is ordinarilystimulated at a location within the neck by first surgically implantingan electrode there and then connecting the electrode to an electricalstimulator [U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis,to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve stimulationtechniques for treatment of epileptic seizures, to OSORIO et al; U.S.Pat. No. 5,299,569 entitled Treatment of neuropsychiatric disorders bynerve stimulation, to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S.Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation andtranscranial stimulation: An overview of stimulation parameters andneurotransmitter release. Neuroscience and Biobehavioral Reviews 33(2009) 1042-1060; GROVES DA, Brown V J. Vagal nerve stimulation: areview of its applications and potential mechanisms that mediate itsclinical effects. Neurosci Biobehav Rev 29(2005):493-500; Reese TERRY,Jr. Vagus nerve stimulation: a proven therapy for treatment of epilepsystrives to improve efficacy and expand applications. Conf Proc IEEE EngMed Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nervestimulation: current concepts. Neurosurg Focus 25 (3, 2008):E9, pp. 1-4;ANDREWS, R. J. Neuromodulation. I. Techniques-deep brain stimulation,vagus nerve stimulation, and transcranial magnetic stimulation. Ann. N.Y. Acad. Sci. 993(2003): 1-13; LABINER, D. M., Ahern, G. L. Vagus nervestimulation therapy in depression and epilepsy: therapeutic parametersettings. Acta. Neurol. Scand. 115(2007): 23-33].

Many such therapeutic applications of electrical stimulation involve thesurgical implantation of electrodes within a patient. In contrast,devices used for the medical procedures that are disclosed herein do notinvolve surgery. Instead, the present devices and methods stimulatenerves by transmitting energy to nerves and tissue non-invasively. Amedical procedure is defined as being non-invasive when no break in theskin (or other surface of the body, such as a wound bed) is createdthrough use of the method, and when there is no contact with an internalbody cavity beyond a body orifice (e.g, beyond the mouth or beyond theexternal auditory meatus of the ear). Such non-invasive procedures aredistinguished from invasive procedures (including minimally invasiveprocedures) in that the invasive procedures insert a substance or deviceinto or through the skin (or other surface of the body, such as a woundbed) or into an internal body cavity beyond a body orifice.

For example, transcutaneous electrical stimulation of a nerve isnon-invasive because it involves attaching electrodes to the skin, orotherwise stimulating at or beyond the surface of the skin or using aform-fitting conductive garment, without breaking the skin [ThierryKELLER and Andreas Kuhn. Electrodes for transcutaneous (surface)electrical stimulation. Journal of Automatic Control, University ofBelgrade 18(2, 2008):35-45; Mark R. PRAUSNITZ. The effects of electriccurrent applied to skin: A review for transdermal drug delivery.Advanced Drug Delivery Reviews 18 (1996) 395-425]. In contrast,percutaneous electrical stimulation of a nerve is minimally invasivebecause it involves the introduction of an electrode under the skin, vianeedle-puncture of the skin.

Another form of non-invasive electrical stimulation is magneticstimulation. It involves the induction, by a time-varying magneticfield, of electrical fields and current within tissue, in accordancewith Faraday's law of induction. Magnetic stimulation is non-invasivebecause the magnetic field is produced by passing a time-varying currentthrough a coil positioned outside the body, An electrice field isinduced at a distance causing electric current to flow withinelectrically conducting bodily tissue. The electrical circuits formagnetic stimulators are generally complex and expensive and use a highcurrent impulse generator that may produce discharge currents of 5,000amps or more, which is passed through the stimulator coil to produce amagnetic pulse. The principles of electrical nerve stimulation using amagnetic stimulator, along with descriptions of medical applications ofmagnetic stimulation, are reviewed in: Chris HOVEY and Reza Jalinous,The Guide to Magnetic Stimulation, The Magstim Company Ltd, SpringGardens, Whitland, Carmarthenshire, SA34 0HR, United Kingdom, 2006. Incontrast, the magnetic stimulators that are disclosed herein arerelatively simpler devices that use considerably smaller currents withinthe stimulator coils. Accordingly, they are intended to satisfy the needfor simple-to-use and less expensive non-invasive magnetic stimulationdevices, for use in treating dementia, as well as use in treating otherconditions.

Potential advantages of such non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures are generally painless and may be performedwithout the dangers and costs of surgery. They are ordinarily performedeven without the need for local anesthesia. Less training may berequired for use of non-invasive procedures by medical professionals. Inview of the reduced risk ordinarily associated with non-invasiveprocedures, some such procedures may be suitable for use by the patientor family members at home or by first-responders at home or at aworkplace. Furthermore, the cost of non-invasive procedures may besignificantly reduced relative to comparable invasive procedures.

In the present invention, noninvasive vagus nerve electrical stimulationand/or magnetic stimulation are used to treat neurodegenerativediseases. Neurodegenerative diseases result from the deterioration ofneurons, causing brain dysfunction. The diseases are loosely dividedinto two groups—conditions affecting memory that are ordinarily relatedto dementia and conditions causing problems with movements. The mostwidely known neurodegenerative diseases include Alzheimer (orAlzheimer's) disease and its precursor mild cognitive impairment (MCI),Parkinson's disease (including Parkinson's disease dementia), andmultiple sclerosis.

Less well-known neurodegenerative diseases include adrenoleukodystrophy,AIDS dementia complex, Alexander disease, Alper's disease, amyotrophiclateral sclerosis (ALS), ataxia telangiectasia, Batten disease, bovinespongiform encephalopathy, Canavan disease, cerebral amyloid angiopathy,cerebellar ataxia, Cockayne syndrome, corticobasal degeneration,Creutzfeldt-Jakob disease, diffuse myelinoclastic sclerosis, fatalfamilial insomnia, Fazio-Londe disease, Friedreich's ataxia,frontotemporal dementia or lobar degeneration, hereditary spasticparaplegia, Huntington disease, Kennedy's disease, Krabbe disease, Lewybody dementia, Lyme disease, Machado-Joseph disease, motor neurondisease, Multiple systems atrophy, neuroacanthocytosis, Niemann-Pickdisease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateralsclerosis including its juvenile form, progressive bulbar palsy,progressive supranuclear palsy, Refsum's disease including its infantileform, Sandhoff disease, Schilder's disease, spinal muscular atrophy,spinocerebellar ataxia, Steele-Richardson-Olszewski disease, subacutecombined degeneration of the spinal cord, survival motor neuron spinalmuscular atrophy, Tabes dorsalis, Tay-Sachs disease, toxicencephalopathy, transmissible spongiform encephalopathy, Vasculardementia, and X-linked spinal muscular atrophy, as well as idiopathic orcryptogenic diseases as follows: synucleinopathy, progranulinopathy,tauopathy, amyloid disease, prion disease, protein aggregation disease,and movement disorder. A more comprehensive listing may be found at theweb site (www) of the National Institute of Neurological Disorders andStroke (ninds) of the National Institutes of Health (nih) of the UnitedStates government (gov). It is understood that such diseases often go bymore than one name and that a disease classification may oversimplifypathologies that occur in combination or that are not archetypical.

Despite the fact that at least some aspect of the pathology of each ofthe neurodegenerative diseases mentioned above is different from theother diseases, their pathologies ordinarily share other features, sothat they may be considered as a group. Furthermore, aspects of theirpathologies that they have in common often make it possible to treatthem with similar therapeutic methods. Thus, many publications describefeatures that neurodegenerative diseases have in common [Dale E.BREDESEN, Rammohan V. Rao and Patrick Mehlen. Cell death in the nervoussystem. Nature 443(2006): 796-802; Christian HAASS. Initiation andpropagation of neurodegeneration. Nature Medicine 16(11, 2010):1201-1204; Eng H L O. Degeneration and repair in central nervous systemdisease. Nature Medicine 16(11, 2010):1205-1209; Daniel M. SKOVRONSKY,Virginia M.-Y. Lee, and John Q. TROJANOWSKI. Neurodegenerative Diseases:New Concepts of Pathogenesis and Their Therapeutic Implications. Annu.Rev. Pathol. Mech. Dis. 1(2006): 151-70; Michael T. LIN and M. FlintBeal. Mitochondrial dysfunction and oxidative stress inneurodegenerative diseases. Nature 443(2006): 787-795; Jorge J. PALOP,Jeannie Chin and Lennart Mucke. A network dysfunction perspective onneurodegenerative diseases. Nature 443(2006): 768-773; David C.RUBINSZTEIN. The roles of intracellular protein-degradation pathways inneurodegeneration. Nature 443(2006): 780-786].

The present invention is concerned primarily with the treatment of aparticular class of neurodegenerative disease, namely, neurodegenerativedementias, among which Alzheimer (or Alzheimer's) disease (AD) is themost prevalent. However, it is understood that according to the previousparagraph, treatments that are disclosed here might be applicable toother neurodegenerative diseases as well.

Dementia is a clinical diagnosis that is based on evidence of cognitivedysfunction in both the patient's history and in successive mentalstatus examinations. The diagnosis is made when there is impairment intwo or more of the following: learning and retaining newly acquiredinformation (episodic declarative memory); handling complex tasks andreasoning abilities (executive cognitive functions); visuospatialability and geographic orientation; and language functions. Thediagnosis may be made after excluding potentially treatable disordersthat may otherwise contribute to cognitive impairment, such asdepression, vitamin deficiencies, hypothyroidism, tumor, subduralhematomas, central nervous system infection, a cognitive disorderrelated to human immunodeficiency virus infection, adverse effects ofprescribed medications, and substance abuse [McKHANN G, Drachman D,Folstein M, Katzman R, Price D, Stadlan E M. Clinical diagnosis ofAlzheimer's disease: report of the NINCDS-ADRDA Work Group under theauspices of Department of Health and Human Services Task Force onAlzheimer's Disease. Neurology 34(7, 1984):939-44; David S. KNOPMAN.Alzheimer's Disease and other dementias. Chapter 409 (pp. 2274-2283) In:Goldman's Cecil Medicine, 24th Edn. (Lee Goldman and Andrew I. Schafer,Eds.). Philadelphia: Elsevier-Saunders, 2012; THOMPSON S B. AlzheimersDisease: Comprehensive Review of Aetiology, Diagnosis, AssessmentRecommendations and Treatment. Webmed Central AGING 2011; 2(3):WMC001681, pp. 1-42].

Dementia prevalence increases with age, from 5% of those aged 71-79years to 37% of those aged 90 and older. However, despite theirprevalence in old age, dementias such as Alzheimer's disease are not anintegral part of the aging process [NELSON P T, Head E, Schmitt F A,Davis P R, Neltner J H, Jicha G A, Abner E L, Smith C D, Van Eldik L J,Kryscio R J, Scheff S W. Alzheimer's disease is not “brain aging”:neuropathological, genetic, and epidemiological human studies. ActaNeuropathol 121(5, 2011):571-87]. Genetics plays a role in early-onsetAD (less than 1% of cases). The most powerful genetic risk factor forthe more common forms of AD is the APOE e4 gene, one or more copies ofwhich are carried by 60% of AD patients in some populations. Otherwise,the risk of AD may be increased by a low level of education, severe headinjury, cerebrovascular disease, diabetes and obesity.

In the United States, the average annual cost of caring for a personwith dementia in 2010 was $60,090. The total estimated worldwide annualcosts of dementia were $604 billion in 2010, which exceeded the entiregross national product of Indonesia, Belgium, or Sweden [PLASSMAN B L,Langa K M, Fisher G G, Heeringa S G, Weir D R, Ofstedal M B, Burke J R,Hurd M D, Potter G G, Rodgers W L, Steffens D C, Willis R J, Wallace RB. Prevalence of dementia in the United States: the aging, demographics,and memory study. Neuroepidemiology 29(1-2, 2007):125-32; Anders WIMOand Martin Prince. Alzheimer's Disease International World AlzheimerReport 2010. The Global Economic Impact of Dementia. pp. 1-56.Alzheimer's Disease International (ADI). 64 Great Suffolk Street LondonSE 1 0BL, UK].

The principal diseases that cause dementia are three neurodegenerativediseases (Alzheimer's disease, Lewy body disease, and frontotemporallobar degeneration) and cerebrovascular disease. In the United States,Alzheimer's disease accounts for approximately 70% of cases of dementia,and vascular dementia accounts for 17% of cases. Lewy body dementia andfrontotemporal lobar dementia account for the remaining 13% of cases,along with less common causes (e.g., alcoholic/toxic dementia, traumaticbrain injury, normal-pressure hydrocephalus, Parkinson's dementia,Creutzfeldt-Jakob disease, and undetermined etiology). In absolutenumbers, 5.4 million Americans are currently living with Alzheimer'sdisease, and Lewy Body dementia affects 1.3 million Americans.

Patients with each type of dementia exhibit certain typical symptoms. InAlzheimer's disease, anterograde amnesia is a dominant symptom—loss ofthe ability to create new memories of events occurring after the onsetof the disease. Dementia with Lewy bodies is characterized byparkinsonism, visual hallucinations, and a rapid-eye-movement sleepdisorder. Frontotemporal lobar degeneration is characterized byprominent behavioral and personality changes or by prominent languagedifficulties early in the course of the disease.

Cerebrovascular dementia, which may be a sequela of atherosclerosis, isdue to one or more cerebral infarctions (ischemic strokes) in brainlocations that are responsible for the cognitive deficits. Thesimultaneous presence of Alzheimer's disease with vascular dementia iscommon, and it may be difficult to distinguish these two dementia on thebasis of symptoms alone.

Hour-to-hour and day-to-day changes in cognition may also be exhibitedby individuals with dementia. Thus, caregivers of patients with dementiaoften notice that the patient may be confused and incoherent at onetime, and only a few hours later, or the next day, the patient is alertand coherent. The time-course and situational antecedent of thoseso-called cognitive fluctuations may also be helpful in distinguishingone form of dementia from the others, using clinical scales have beendeveloped to analyze such fluctuations (Clinician Assessment ofFluctuation, One Day Fluctuation Assessment Scale, Mayo FluctuationQuestionnaire). Dementia with Lewy bodies is associated with transientand spontaneous episodes of confusion and an inability to engage inmeaningful cognitive activity, followed by reversion to a near normallevel of function, often within hours. In contrast, cognitivefluctuations in Alzheimer's disease are often elicited by situations inwhich an underlying cognitive impairment manifests itself, typically asrepetitiveness in conversation, forgetfulness in relation to a recenttask or event, or other behavioral consequences of poor memory. Inaddition to this situational triggering aspect of a cognitivefluctuation in patients with Alzheimer's disease, the confusion is oftena more enduring state shift (good days/bad days), rather than anhour-to-hour shift.

The mechanism of cognitive fluctuation is unknown, either for thehour-to-hour type that is common in dementia with Lewy bodies, or theday-to-day type that is not uncommon among Alzheimer patients. However,the mechanism is clearly different than the ones involved in circadianphenomena, such as “sundowning,” because the cognitive fluctuation neednot occur around a particular time of day. Whatever the mechanism ofcognitive fluctuations, it would be very beneficial to be able toprevent or reverse them, if only as a prophylactic or symptomatictreatment, so as to spare the patient and caregiver of the stressassociated with fluctuating cognitive impairment as it relates toimpairment of activities of daily living [Jorge J. PALOP, Jeannie Chinand Lennart Mucke. A network dysfunction perspective onneurodegenerative diseases. Nature 443(7113, 2006):768-73; WALKER M P,Ayre G A, Cummings J L, Wesnes K, McKeith I G, O'Brien J T, Ballard C G.The Clinician Assessment of Fluctuation and the One Day FluctuationAssessment Scale. Two methods to assess fluctuating confusion indementia. Br J Psychiatry 177(2000):252-6; BRADSHAW J, Saling M, HopwoodM, Anderson V, Brodtmann A. Fluctuating cognition in dementia with Lewybodies and Alzheimer's disease is qualitatively distinct. J NeurolNeurosurg Psychiatry 75(3, 2004):382-7; BALLARD C, Walker M, O'Brien J,Rowan E, McKeith I. The characterisation and impact of ‘fluctuating’cognition in dementia with Lewy bodies and Alzheimer's disease. Int JGeriatr Psychiatry 16(5, 2001):494-8; CUMMINGS J L. Fluctuations incognitive function in dementia with Lewy bodies. Lancet Neurol 3(5,2004):266; David R. LEE, John-Paul Taylor, Alan J. Thomas. Assessment ofcognitive fluctuation in dementia: a systematic review of theliterature. International Journal of Geriatric Psychiatry 27(10, 2012):989-998; BACHMAN D, Rabins P. “Sundowning” and other temporallyassociated agitation states in dementia patients. Annu Rev Med57(2006):499-511].

As described above, dementia is a clinical diagnosis that is based onevidence of cognitive dysfunction in both the patient's history and insuccessive mental status examinations. With the ability to better stagethe progression of dementia, treatment might be justified at stagesprior to actual onset of the dementia. In particular, the presentinvention might best be used early in the course of the diseaseprogression, such that treatment could be directed to slowing, stopping,or even reversing the pathophysiological processes underlying thedementia. Thus, the present invention contemplates treatments even whenthe patient exhibits prodromal symptoms or when the patient has beendiagnosed with mild cognitive impairment (MCI) [DeCARLI C. Mildcognitive impairment: prevalence, prognosis, aetiology, and treatment.Lancet Neurol 2(1, 2003):15-21; MAYEUX R. Clinical practice. EarlyAlzheimer's disease. N Engl J Med 362(23, 2010):2194-2201; WILSON R S,Leurgans S E, Boyle P A, Bennett D A. Cognitive decline in prodromalAlzheimer disease and mild cognitive impairment. Arch Neurol 68(3,2011):351-356].

Early staging of the patient's disease progression makes use ofbiomarkers, which are cognitive, physiological, biochemical, andanatomical variables that can be measured in a patient that indicate theprogression of a dementia such as AD. The most commonly measuredbiomarkers for AD include decreased Aß42 in the cerebrospinal fluid(CSF), increased CSF tau, decreased fluorodeoxyglucose uptake on PET(FDG-PET), PET amyloid imaging, and structural MRI measures of cerebralatrophy. Use of biomarkers to stage AD has developed to the point thatbiomarkers can be used with revised criteria for diagnosing the disease[MASDEU J C, Kreisl W C, Berman K F. The neurobiology of Alzheimerdisease defined by neuroimaging. Curr Opin Neurol 25(4, 2012):410-420;DUBOIS B, Feldman H H, Jacova C, Dekosky S T, Barberger-Gateau P,Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K,O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer'sdisease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6(8,2007):734-46; GAUTHIER S, Dubois B, Feldman H, Scheltens P. Revisedresearch diagnostic criteria for Alzheimer's disease. Lancet Neurol 7(8, 2008): 668-670].

In the remainder of this background section, current methods of treatingAD are described. As summarized here, they include methods to treatcognitive symptoms of AD patients, as well as methods that are intendedto treat the underlying pathophysiological progression of AD. Becausethe methods described in the publications cited below have not beendemonstrated to exhibit more than very modest success in treating onlysymptoms of AD, and no method is known to stop the progression of AD,additional methods are clearly needed, which motivates the inventionthat is disclosed here. Because the disclosure involves vagus nervestimulation, the effect of stimulation on the patient's locus ceruleus,and consequences of that effect, the literature relevant to thosesubjects is emphasized in what follows.

Before the currently favored amyloid cascade hypothesis of AD (andsubsequent variants of that hypothesis), the focus of AD research wasthe search for a clearly defined neurochemical abnormality in ADpatients, which would provide the basis for the development of rationaltherapeutic interventions that are analogous to levodopa treatment ofParkinson's disease. This led to the cholinergic hypothesis ofAlzheimer's disease, which proposed that degeneration of cholinergicneurons in the basal forebrain and the associated loss of cholinergicneurotransmission in the cerebral cortex and other areas contributedsignificantly to the deterioration in cognitive function seen inpatients with Alzheimer's disease. The symptomatic drug treatments thatarose from that research are currently the mainstay of AD treatment,even though their effectiveness is very modest, and no drug delays theprogression of the disease. Approved drugs for the symptomatic treatmentof AD modulate neurotransmitters—either acetylcholine or glutamate:cholinesterase inhibitors (tacrine, rivastigmine, galantamine anddonepezil) and partial N-methyl-D-aspartate antagonists (memantine)[FRANCIS P T, Ramirez M J, Lai M K. Neurochemical basis for symptomatictreatment of Alzheimer's disease. Neuropharmacology 59(4-5,2010):221-229; FRANCIS P T, Palmer A M, Snape M, Wilcock G K. Thecholinergic hypothesis of Alzheimer's disease: a review of progress. JNeurol Neurosurg Psychiatry 66(2, 1999):137-47; MESULAM M. Thecholinergic lesion of Alzheimer's disease: pivotal factor or side show?Learn Mem 11(1, 2004):43-49].

The symptomatic treatment of AD by modulating neurotransmitters otherthan acetylcholine or glutamate has also been considered. One suchneurotransmitter is norepinephrine (noradrenaline), which in the brainis principally synthesized in the locus ceruleus. A rationale fortherapeutic modulation of norepinephrine levels has been that in AD,there is loss of noradrenergic neurons in the locus ceruleus, and thetreatment would compensate for that loss [HAGLUND M, Sjöbeck M, EnglundE. Locus ceruleus degeneration is ubiquitous in Alzheimer's disease:possible implications for diagnosis and treatment. Neuropathology 26(6,2006):528-32; SAMUELS E R, Szabadi E. Functional neuroanatomy of thenoradrenergic locus coeruleus: its roles in the regulation of arousaland autonomic function part II: physiological and pharmacologicalmanipulations and pathological alterations of locus coeruleus activityin humans. Curr Neuropharmacol 6(3, 2008):254-85; Patricia SZOT. Commonfactors among Alzheimer's disease, Parkinson's disease, and epilepsy:Possible role of the noradrenergic nervous system. Epilepsia 53(Suppl.1, 2012):61-66].

Accordingly, several investigators proposed to increase brainnorepinephrine as a therapy for AD patients [E M VAZEY, V K Hinson, A CGranholm, M A Eckert, G A Jones. Norepinephrine in Neurodegeneration: ACoerulean Target. J Alzheimers Dis Parkinsonism 2(2, 2012):1000e114, pp.1-3]. Administration of norepinephrine itself is not feasible as amethod for increasing its levels in the central nervous system becausenorepinephrine, as with other catecholamines, cannot cross theblood-brain barrier. Many other drugs such as amphetamines andmethylphenidate can increase norepinephrine brain levels, but theyaffect other neurotransmitter systems as well and have significant sideeffects. Consequently, less direct methods have been used or suggestedas ways to increase norepinephrine levels in the central nervous system,or to activate adrenergic signaling. They include the use of specialdrugs that mimic norepinephrine, that serve as precursors ofnorepinephrine, that block the reuptake of norepinephrine, and thatserve as adrenoceptor antagonists that enhances norepinephrine release[MISSONNIERP, Ragot R, Derouesné C, Guez D, Renault B. Automaticattentional shifts induced by a noradrenergic drug in Alzheimer'sdisease: evidence from evoked potentials. Int J Psychophysiol 33(3,1999): 243-51; FRIEDMAN J I, Adler D N, Davis K L. The role ofnorepinephrine in the pathophysiology of cognitive disorders: potentialapplications to the treatment of cognitive dysfunction in schizophreniaand Alzheimer's disease. Biol Psychiatry. 46(9, 1999):1243-52; KALININS, Polak P E, Lin S X, Sakharkar A J, Pandey S C, Feinstein D L. Thenoradrenaline precursor L-DOPS reduces pathology in a mouse model ofAlzheimer's disease. Neurobiol Aging 33(8, 2012):1651-1663; MOHS, R. C.,Shiovitz, T. M., Tariot, P. N., Porsteinsson, A. P., Baker, K. D.,Feldman, P. D., 2009. Atomoxetine augmentation of cholinesteraseinhibitor therapy in patients with Alzheimer disease: 6-month,randomized, double-blind, placebo-controlled, parallel-trial study. Am.J. Geriatr. Psychiatry 17, 752-759; SCULLION G A, Kendall D A, Marsden CA, Sunter D, Pardon M C. Chronic treatment with the a2-adrenoceptorantagonist fluparoxan prevents age-related deficits in spatial workingmemory in APP×PS1 transgenic mice without altering

-amyloid plaque load or astrocytosis. Neuropharmacology 60(2-3,2011):223-34]. Other agents that are thought to alter norepinephrinelevels, via locus ceruleus activity, include chronic stress, chronicopiate treatment, and anti-depressant treatment [NESTLER E J, Alreja M,Aghajanian G K. Molecular control of locus coeruleus neurotransmission.Biol Psychiatry 46(9, 1999):1131-1139; SAMUELS, E. R., and Szabadi, E.Functional neuroanatomy of the noradrenergic locus coeruleus: its rolesin the regulation of arousal and autonomic function part II:physiological and pharmacological manipulations and pathologicalalterations of locus coeruleus activity in humans. Curr. Neuropharmacol.6(2008), 254-285].

However, for several reasons, it is not settled that apharmacologically-induced increase of norepinephrine, or increasedsignaling through the adrenergic receptors in the central nervoussystem, will substantially benefit AD patients. First, in patients withAD, clonidine (a centrally acting alpha2 adrenergic agonist) wasreported to have no effect on cognitive functions, and may even impairsustained attention and memory. Another putative alpha2-adrenoceptoragonist, guanfacine, has consistently been shown to be without effect oncognitive functions. Thus, administration of clonidine or guanfacinedoes not appear to provide any consistent improvement in cognitivefunctions, either in normal subjects or in patients with AD or othercognitive impairments. On the other hand, the alpha2-adrenoceptorantagonist, idazoxan, improved planning, sustained attention, verbalfluency, and episodic memory but impaired spatial working memory inpatients with dementia of the frontal type [MARIENMR, Colpaert F C,Rosenquist A C. Noradrenergic mechanisms in neurodegenerative diseases:a theory. Brain Res Brain Res Rev 45(1, 2004):38-78].

Second, norepinephrine significantly worsens agitation and anxiety in ADpatients, such that any potential benefits of increased norepinephrinelevels may be offset by behavioral side effects, as well ascardiovascular side effects [HERRMANN N, Lanctot K L, Khan L R. The roleof norepinephrine in the behavioral and psychological symptoms ofdementia. J Neuropsychiatry Clin Neurosci 16(3, 2004):261-76; PESKIND,E. R., Tsuang, D. W., Bonner, L. T., Pascualy, M., Riekse, R. G.,Snowden, M. B., Thomas, R., Raskind, M. A. Propranolol for disruptivebehaviors in nursing home residents with probable or possible Alzheimerdisease: a placebo-controlled study. Alzheimer Dis. Assoc. Disord.19(2005): 23-28].

Third, loss of locus ceruleus cells in AD may lead to compensatoryproduction of norepinephrine in other cells, such that there mayactually be an increase in norepinephrine levels in some AD patients[Fitzgerald P J. Is elevated norepinephrine an etiological factor insome cases of Alzheimer's disease? Curr Alzheimer Res 7(6, 2010):506-16;ELROD R, Peskind E R, DiGiacomo L, Brodkin K I, Veith R C, Raskind M A.Effects of Alzheimer's disease severity on cerebrospinal fluidnorepinephrine concentration. Am J Psychiatry 154(1, 1997):25-30].

Even if there is a decrease in overall brain norepinephrine levels inAD, this decrease does not necessarily occur uniformly among brainregions that are modulated by the locus ceruleus, and patterns ofcompensatory receptor alterations may also be complicated, withselective decreases and increases of noradrenergic receptors subtypes indifferent regions of the brain [HOOGENDIJK W J, Feenstra M G, BotterblomM H, Gilhuis J, Sommer I E, Kamphorst W, Eikelenboom P, Swaab D F.Increased activity of surviving locus ceruleus neurons in Alzheimer'sdisease. Ann Neurol 45(1, 1999):82-91; SZOT P, White S S, Greenup J L,Leverenz J B, Peskind E R, Raskind M A. Compensatory changes in thenoradrenergic nervous system in the locus coeruleus and hippocampus ofpostmortem subjects with Alzheimer's disease and dementia with LewyBodies. J Neurosci 26(2006):467-478; SZOT P, White S S, Greenup J L,Leverenz J B, Peskind E R, Raskind M A. Changes in adrenoreceptors inthe prefrontal cortex of subjects with dementia: evidence ofcompensatory changes. Neuroscience 146(2007):471-480].

Therefore, what is needed is not a pharmacological method that increasesnorepinephrine levels indiscriminately throughout the central nervoussystem of AD patients, but rather a method that can selectively increase(or decrease) the norepinephrine levels only where it is needed. This istrue whether the increase is intended to improve cognition or whetherthe increase in norepinephrine levels is intended to prevent, delay orantagonize pathological biochemical changes that occur in the brains ofAD patients [COUNTS S E, Mufson E J. Noradrenaline activation ofneurotrophic pathways protects against neuronal amyloid toxicity. JNeurochem 113(3, 2010):649-60; WENK G L, McGann K, Hauss-Wegrzyniak B,Rosi S. The toxicity of tumor necrosis factor-alpha upon cholinergicneurons within the nucleus basalis and the role of norepinephrine in theregulation of inflammation: implications for Alzheimer's disease.Neuroscience 121(3, 2003):719-29; KALININ S, Gavrilyuk V, Polak P E,Vasser R, Zhao J, Heneka M T, Feinstein D L. Noradrenaline deficiency inbrain increases beta-amyloid plaque burden in an animal model ofAlzheimer's disease. Neurobiol Aging 28(8, 2007):1206-1214; HENEKA M T,Ramanathan M, Jacobs A H, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T,Sastre M, Galldiks N, Zimmer A, Hoehn M, Heiss W D, Klockgether T,Staufenbiel M. Locus ceruleus degeneration promotes Alzheimerpathogenesis in amyloid precursor protein 23 transgenic mice. JNeurosci. 26(5, 2006):1343-54; HENEKA M T, Nadrigny F, Regen T,Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-KurutzD, Walter J, Kirchhoff F, Hanisch U K, Kummer M P. Locus ceruleuscontrols Alzheimer's disease pathology by modulating microglialfunctions through norepinephrine. Proc Natl Acad Sci USA. 107(13,2010):6058-6063; JARDANHAZI-KURUTZ D, Kummer M P, Terwel D, Vogel K,Thiele A, Heneka M T. Distinct adrenergic system changes andneuroinflammation in response to induced locus ceruleus degeneration inAPP/PS1 transgenic mice. Neuroscience 176(2011):396-407; YANG J H, Lee EO, Kim S E, Suh Y H, Chong Y H. Norepinephrine differentially modulatesthe innate inflammatory response provoked by amyloid-ß peptide viaaction at ß-adrenoceptors and activation of cAMP/PKA pathway in humanTHP-1 macrophages. Exp Neurol 236(2, 2012):199-206; KONG Y, Ruan L, QianL, Liu X, Le Y. Norepinephrine promotes microglia to uptake and degradeamyloid beta peptide through upregulation of mouse formyl peptidereceptor 2 and induction of insulin-degrading enzyme. J Neurosci 30(35,2012):11848-11857; KALININ S, Polak P E, Lin S X, Sakharkar A J, PandeyS C, Feinstein D L. The noradrenaline precursor L-DOPS reduces pathologyin a mouse model of Alzheimer's disease. Neurobiol Aging 33(8,2012):1651-1663; HAMMERSCHMIDT T, Kummer M P, Terwel D, Martinez A,Gorji A, Pape H C, Rommelfanger K S, Schroeder J P, Stoll M, Schultze J,Weinshenker D, Heneka M T. Selective Loss of Noradrenaline ExacerbatesEarly Cognitive Dysfunction and Synaptic Deficits in APP/PS1 Mice. BiolPsychiatry. 2012 Aug. 9. Epub ahead of print, pp. 1-10; O'DONNELL J,Zeppenfeld D, McConnell E, Pena S, Nedergaard M. Norepinephrine: ANeuromodulator That Boosts the Function of Multiple Cell Types toOptimize CNS Performance. Neurochem Res. 2012 Jun. 21. (Epub ahead ofprint}, pp. 1-17].

Psychotropic medications are also used in conjunction with theneurotransmitter modulators to treat secondary symptoms of AD such asdepression, agitation, and sleep disorders [Julius POPP and Sonke Arlt.Pharmacological treatment of dementia and mild cognitive impairment dueto Alzheimer's disease. Current Opinion in Psychiatry 24(2011):556-561;Fadi MASSOUD and Gabriel C Leger. Pharmacological treatment of Alzheimerdisease. Can J Psychiatry. 56(10, 2011):579-588; Carl H. SADOWSKY andJames E. Galvin. Guidelines for the management of cognitive andbehavioral problems in dementia. J Am Board Fam Med 25(2012):350-366].

Therapies based on nutrition, lifestyle modification, herbal or dietarysupplements (e.g., Huperzine A), brain exercises, and other integrativemethods have also been proposed [Dharma Singh KHALSA. Alzheimer Disease.pp. 78-90 (Chapter 9) In: Integrative Medicine, 3rd Ed. (David Rakel,ed.) Philadelphia, Pa.: Elsevier Saunders, 2012; Clive BALLARD, ZuneraKhan, Hannah Clack, and Anne Corbett. Nonpharmacological treatment ofAlzheimer disease. The Canadian Journal of Psychiatry 56(10, 2011):589-595; DAVIGLUS M L, Bell C C, Berrettini W, Bowen P E, Connolly E S,Cox N J, Dunbar-Jacob J M, Granieri E C, Hunt G, McGarry K, Patel D,Potosky A L, Sanders-Bush E, Silberberg D, Trevisan M. NIHState-of-the-Science Conference Statement: Preventing Alzheimer'sDisease and Cognitive Decline. NIH Consens State Sci Statements 27(4,2010), pp. 1-121].

Therapies directed to modifying AD progression itself are consideredinvestigational. These include treatment of the intense inflammationthat occurs in the brains of patients with AD, estrogen therapy, use offree-radical scavengers, therapies designed to decrease toxic amyloidfragments in the brain (vaccination, anti-amyloid antibodies, selectiveamyloid-lowering agents, chelating agents to prevent amyloidpolymerization, brain shunting to improve removal of amyloid, andbeta-secretase inhibitors to prevent generation of the A-beta amyloidfragment), and agents that may prevent or reverse excess tauphosphorylation and thereby diminish formation of neurofibrillarytangles. Some agents, such as retinoids, may target multiple aspects ofAD pathogenesis [TAYEB H O, Yang H D, Price B H, Tarazi F I.Pharmacotherapies for Alzheimer's disease: beyond cholinesteraseinhibitors. Pharmacol Ther 134(1, 2012):8-25; LEMER A J,Gustaw-Rothenberg K, Smyth S, Casadesus G. Retinoids for treatment ofAlzheimer's disease. Biofactors 38(2, 2012):84-89; KURZ A, Perneczky R.Novel insights for the treatment of Alzheimer's disease. ProgNeuropsychopharmacol Biol Psychiatry 35(2, 2011):373-379; MINATI L,Edginton T, Bruzzone M G, Giaccone G. Current concepts in Alzheimer'sdisease: a multidisciplinary review. Am J Alzheimers Dis Other Demen24(2, 2009):95-121].

However, it is increasingly recognized that a single target orpathogenic pathway for the treatment of AD is unlikely to be identified.The best strategy is thought to be a multi-target therapy that includesmultiple types of treatments [MANGIALASCHE F, Solomon A, Winblad B,Mecocci P, Kivipelto M. Alzheimer disease: clinical trials and drugdevelopment. Lancet Neurol 9(7, 2010):702-716]. Targets in thatmulti-target approach will include inflammatory pathways, and severaltherapeutic agents have been proposed to target them—nonsteroidalanti-inflammatory drugs, statins, RAGE antagonists and antioxidants[STUCHBURY G, Munch G. Alzheimer associated inflammation, potential drugtargets and future therapies. J Neural Transm. 2005 March; 112(3):429-53Joseph BUTCHART and Clive Holmes. Systemic and Central Immunity inAlzheimer's Disease: Therapeutic Implications. CNS Neuroscience &Therapeutics 18(2012): 64-76]. Another such agent, Etanercept, targetsTNF-alpha, but its use has the disadvantage that because it does notpass the blood-brain barrier (BBB), its administration is via a painfulspinal route or via an experimental method to get through the BBB [U.S.Pat. No. 7,640,062, entitled Methods and systems for management ofalzheimer's disease, to SHALEV]. One TNF-inhibitor that does not havethis disadvantage is thalidomide [Tweedie D, Sambamurti K, Greig N H:TNF-alpha Inhibition as a Treatment Strategy for NeurodegenerativeDisorders: New Drug Candidates and Targets. Curr Alzheimer Res 2007,4(4):375-8]. However, thalidomide is well known by the public to causebirth defects, and in a small trial, its use did not appear to improvecognition in AD patients [Peggy PECK. IADRD: Pilot Study of Thalidomidefor Alzheimer's Disease Fails to Detect Cognitive Benefit but FindsEffect on TNF-alpha. Doctor's Guide Global Edition, Jul. 26, 2002].

Various devices have been proposed to restore or enhance cognition,including cognition of AD patients [Mijail Demian SERRUYA and Michael J.Kahana. Techniques and devices to restore cognition. Behav Brain Res192(2, 2008): 149-165]. Deep brain electrical stimulation has beengenerally unsuccessful or counterproductive in attempting to enhance thememory of AD patients. However, improved verbal recall has been observedin one case study in which deep-brain stimulation of the hypothalamusand fornix was used to treat morbid obesity [HAMANI C, McAndrews M P,Cohn M, Oh M, Zumsteg D, Shapiro C M, Wennberg R A, Lozano A M. Memoryenhancement induced by hypothalamic/fornix deep brain stimulation. AnnNeurol 63(2008):119-23; Adrian W. LAXTON and Andres M. Lozano. Deepbrain stimulation for the treatment of Alzheimer disease and dementias.World Neurosurg. (2012), pp. 1-8]. Entorhinal, but not hippocampal, deepbrain stimulation has also been found to improve memory used in spatialnavigation. Authors of that investigation suggest that in usingneuroprosthetic devices for purposes of cognitive enhancement,stimulation may not need to be applied continuously, but instead onlywhen patients are attempting to learn important information. They alsosuggest that resetting of the phase of the theta rhythm in the EEG (3-8Hz) improves memory performance, as has been observed in animalexperiments [Nanthia SUTHANA, Zulfi Haneef, John Stern, Roy Mukamel,Eric Behnke, Barbara Knowlton and Itzhak Fried. Memory enhancement anddeep-brain stimulation of the entorhinal area. N Engl J Med366(2012):502-10; LEMON N, Aydin-Abidin S, Funke K, Manahan-Vaughan D.Locus coeruleus activation facilitates memory encoding and induceshippocampal LTD that depends on beta-adrenergic receptor activation.Cereb Cortex 19(12, 2009):2827-37].

Magnetic stimulation of AD patients has also been performed, but its usehas been intended only to affect cognitive skills and only usingtranscranial magnetic stimulation [Mamede de CARVALHO, Alexandre deMendonca, Pedro C. Miranda, Carlos Garcia and Maria Lourdes Sales Luis.Magnetic stimulation in Alzheimer's disease. Journal of Neurology 244(1997, 5): 304-307; COTELLI M, Manenti R, Cappa S F, Zanetti O, MiniussiC. Transcranial magnetic stimulation improves naming in Alzheimerdisease patients at different stages of cognitive decline. Eur J Neurol.15(12, 2008):1286-92; GUSE B, Falkai P, Wobrock T. Cognitive effects ofhigh-frequency repetitive transcranial magnetic stimulation: asystematic review. J Neural Transm. 117(1, 2010):105-22; RaffaeleNARDONE, Jurgen Bergmann, Monica Christova, Francesca Caleri, FredianoTezzon, Gunther Ladurner, Eugen Trinka and Stefan Golaszewski. Effect oftranscranial brain stimulation for the treatment of Alzheimer disease: Areview. International Journal of Alzheimer's Disease 2012, Article ID687909: pp. 1-5; Raffaele NARDONE, Stefan Golaszewski, Gunther Ladurner,Frediano Tezzon, and Eugen Trinka. A Review of Transcranial MagneticStimulation in the in vivo Functional Evaluation of Central CholinergicCircuits in Dementia. Dement Geriatr Cogn Disord 32(2011):18-25].

A method of using vagal nerve stimulation to treat AD symptoms wasdisclosed in U.S. Pat. No. 5,269,303, entitled Treatment of dementia bynerve stimulation, to WERNICKE et al. It is directed to “a symptom ofdementia” which was described as being either paroxysmal activityexhibited in the patient's EEG or the level of alertness of the patient,but not to cognition per se.

In 2002, it was reported that electrical stimulation of the vagus nervehas a beneficial effect on cognition in patients with AD [SJOGREN M J,Hellström P T, Jonsson M A, Runnerstam M, Silander H C, Ben-Menachem E.Cognition-enhancing effect of vagus nerve stimulation in patients withAlzheimer's disease: a pilot study. J Clin Psychiatry 63(11,2002):972-80]. The rationale for that trial was that vagus nervestimulation had previously been found to enhance the cognitive abilitiesof patients that were undergoing vagus nerve stimulation for otherconditions such as epilepsy and depression, as well as enhancedcognitive abilities observed in animal studies. Results concerning theAD patients' improved cognitive abilities over a longer period of time,along with improvement in tau protein of cerebrospinal fluid, weresubsequently reported [MERRILL C A, Jonsson M A, Minthon L, Ejnell H,C-son Silander H, Blennow K, Karlsson M, Nordlund A, Rolstad S,Warkentin S, Ben-Menachem E, Sjögren M J. Vagus nerve stimulation inpatients with Alzheimer's disease: Additional follow-up results of apilot study through 1 year. J Clin Psychiatry. 2006 August;67(8):1171-8]. Those results were immediately greeted with skepticism,particularly the purported changes in tau protein, because there was nocontrol group and the number of patients was small [Theresa DEFINO.Symptoms stable in AD patients who underwent vagus nerve stimulation.Neurology Today 6(21, 2006):14-15].

Stimulation of the vagus nerve to treat at least the symptomaticcognitive aspects of dementia might be more effective than stimulationof nerves found in locations such as the spine, forehead, and earlobes[CAMERON M H, Lonergan E, Lee H. Transcutaneous Electrical NerveStimulation (TENS) for dementia. Cochrane Database of Systematic Reviews2003, Issue 3. Art. No.: CD004032. (2009 update); Erik J. A. SCHERDER,Marijn W. Luijpen, and Koene R. A. van Dijk. Activation of the dorsalraphe nucleus and locus coeruleus by transcutaneous electrical nervestimulation in Alzheimer's disease: a reconsideration ofstimulation-parameters derived from animal studies. Chinese Journal ofPhysiology 46(4, 2003): 143-150]. However, BOON and colleagues disputethe claim that vagus nerve stimulation with prevailing stimulationparameters can enhance even the cognitive abilities of human patients,although they do conclude that such stimulation can improve cognition inanimal models [Paul BOON, Ine Moors, Veerle De Herdt, Kristl Vonck.Vagus nerve stimulation and cognition. Seizure15(2006), 259-263]. Infact, in humans, vagus nerve stimulation impairs cognitive flexibilityand creative thinking [GHACIBEH G A, Shenker J I, Shenal B, Uthman B M,Heilman K M. Effect of vagus nerve stimulation on creativity andcognitive flexibility. Epilepsy Behav 8(4, 2006):720-725]. Furthermore,it has no effect on learning, but it might enhance memory consolidation,which leads to improved retention [GHACIBEH G A, Shenker J I, Shenal B,Uthman B M, Heilman K M. The influence of vagus nerve stimulation onmemory. Cogn Behav Neurol 19(3, 2006):119-22; CLARK K B, Naritoku D K,Smith D C, Browning R A, Jensen R A. Enhanced recognition memoryfollowing vagus nerve stimulation in human subjects. Nature Neurosci2(1999):94-98]. Among different types of memories, vagus nervestimulation is reported to improve only verbal recognition memory[McGLONE J, Valdivia I, Penner M, Williams J, Sadler R M, Clarke D B.Quality of life and memory after vagus nerve stimulator implantation forepilepsy. Can J Neurol Sci 35(3, 2008):287-96]. However, most suchinvestigations have been performed on patients with electrodes implantedto control epilepsy, so patients with Alzheimer's disease were notincluded in the studies.

The effects of vagus nerve stimulation on the cognition of animal modelsare given in experiments described in the following publications. Theanimal experiments show generally that it may be possible to promotecognition using vagus nerve stimulation, which suggests that failure inthe above-mentioned human experiments might be attributable to usingstimulation parameters that treat epilepsy or depression, instead ofparameters that preferentially enhance cognition. Vagus nervestimulation was shown to activate the locus ceruleus and to increasenorepinephrine output into the basolateral amygdala and hippocampus inrats [NARITOKU D K, Terry W J, Helfert R H. Regional induction of fosimmunoreactivity in the brain by anticonvulsant stimulation of the vagusnerve. Epilepsy Res 22(1, 1995):53-62; HASSERT D L, Miyashita T,Williams C L. The effects of peripheral vagal nerve stimulation at amemory-modulating intensity on norepinephrine output in the basolateralamygdala. Behav Neurosci 118(1, 2004):79-88; CHEN C C, Williams C L.Interactions between epinephrine, ascending vagal fibers, and centralnoradrenergic systems in modulating memory for emotionally arousingevents. Front Behav Neurosci 6:35. Epub 2012 Jun. 28, pp. 1-20].

In a rat model of traumatic brain injury, it was shown that vagus nervestimulation facilitated both the rate of recovery and the extent ofmotor and cognitive recovery [SMITH D C, Modglin A A, Roosevelt R W,Neese S L, Jensen R A, Browning R A, et al. Electrical stimulation ofthe vagus nerve enhances cognitive and motor recovery following moderatefluid percussion injury in the rat. J Neurotrauma 22(12,2005):1485-1502]. Electrical stimulation of the vagus nerve (VNS)delivered at a moderate intensity following a learning experienceenhances memory in laboratory rats, while VNS at lower or higherintensities has little or no effect, which appears to involve modulatingsynaptic plasticity in the hippocampus [ZUO Y, Smith D C, Jensen R A.Vagus nerve stimulation potentiates hippocampal LTP in freely movingrats. Physiol Behav 90(4, 2007):583-589]. More generally, vagus nervestimulation modulates norepinephrine levels via effects on the locusceruleus [DORR A E, Debonnel G. Effect of vagus nerve stimulation onserotonergic and noradrenergic transmission. J Pharmacol Exp Ther 318(2,2006):890-898; MANTA S, Dong J, Debonnel G, Blier P. Enhancement of thefunction of rat serotonin and norepinephrine neurons by sustained vagusnerve stimulation. J Psychiatry Neurosci 34(4, 2009):272-80; SHEN H,Fuchino Y, Miyamoto D, Nomura H, Matsuki N. Vagus nerve stimulationenhances perforant path-CA3 synaptic transmission via the activation ofß-adrenergic receptors and the locus coeruleus. Int JNeuropsychopharmacol 15(4, 2012):523-30].

Otherwise, the only mechanism by which vagus nerve stimulation has beensuggested to affect synaptic activity (e.g., seizures) is via its effecton cerebral circulation [HENRY T R, Bakay R A, Pennell P B, Epstein C M,Votaw J R. Brain blood-flow alterations induced by therapeutic vagusnerve stimulation in partial epilepsy: II. prolonged effects at high andlow levels of stimulation. Epilepsia 45(9, 2004):1064-1070].

In a commonly assigned, co-pending patent application (Publication US20110152967, entitled Non-invasive treatment of neurodegenerativedisease, to SIMON et al), Applicants disclosed six novel mechanisms bywhich stimulation of the vagus nerve may be used to treat the underlyingpathophysiology of AD: (1) stimulate the vagus nerve in such a way as toenhance the availability or effectiveness of TGF-beta or otheranti-inflammatory cytokines; (2) stimulate the vagus nerve in such a wayas to enhance the availability or effectiveness of retinoic acid; (3)stimulate the vagus nerve in such a way as to promote the expression ofthe neurotrophic factors such as BDNF; (4) stimulate the vagus nerve tomodulate the capacity of TNF-alpha to function as a gliotransmitter,including modulating the activity of the cells between which TNF-relatedgliotransmission occurs; (5) stimulate the vagus nerve to modulate thedegradation of TNF-alpha, and/or modify the activity of existingTNF-alpha molecules as a pro-inflammatory mediator; and (6) stimulatethe vagus nerve in such a way as to suppress the release oreffectiveness of pro-inflammatory cytokines, through a mechanism that isdistinct from the one proposed by TRACEY and colleagues. Thus, U.S. Pat.Nos. 6,610,713 and 6,838,471, entitled Inhibition of inflammatorycytokine production by cholinergic agonists and vagus nerve stimulation,to TRACEY, mention treatment of neurodegenerative diseases within a longlist of diseases, in connection with the treatment of inflammationthrough stimulation of the vagus nerve. However, there is no mention orsuggestion by TRACEY that his methods are intended to modulate theactivity of anti-inflammatory cytokines, and in fact, his disclosuresdisclaim a role for antiinflammatory cytokines as mediators ofinflammation through stimulation of the vagus nerve.

In the present application, additional methods and devices for thetreatment or prevention of dementia, particularly Alzheimer's disease,are disclosed. The disclosed method does not increase norepinephrinelevels indiscriminately throughout the CNS of AD patients, but insteadpreferentially increases the norepinephrine levels where it is needed,through selection of appropriate vagus nerve stimulation parameters,which may be adjusted on an individualized basis and on the basis ofprogression of the disease. The method prevents loss of the locusceruleus and takes into account the existence of so-called resting statebrain networks, particularly the default mode network and the ventralattention network. According to the invention, site-preferentialmodulation of norepinephrine levels by vagus nerve stimulation prevents,delays or antagonizes pathological biochemical changes that occur in thebrains of AD patients and that lead to a loss of locus ceruleus cells.The stimulation may also enhance cognition, particularly in patients whoare experiencing cognitive fluctuations.

SUMMARY OF THE INVENTION

The present invention involves devices and methods for the treatment ofdementia, particularly Alzheimer's disease (AD). In certain aspects ofthe invention, a device or system comprises an energy source of magneticand/or electrical energy that is transmitted non-invasively to, or inclose proximity to, a selected nerve of the patient to temporarilystimulate, block and/or modulate the signals in the selected nerve. Inpreferred embodiments of the invention, the selected nerve is a vagusnerve.

A novel mechanism of action for benefiting AD patients, as well aspatients with a precursor of AD (e.g., mild cognitive impairment), isbased on the use of vagus nerve stimulation to induce the release ofincreased quantities of norepinephrine from projections of a patient'slocus ceruleus. Norepinephrine is known to strongly suppressneuroinflammation in the central nervous system (CNS), andneuroinflammation directed against beta amyloid is a primary driver ofneuronal loss in AD. According to the invention, normal levels ofnorepinephrine in the CNS maintain a tolerance of beta amyloid, which isalso present in without AD.

However, in AD, the terminal fields of norepinephrine-releasing locusceruleus cells that innervate those brain regions containing betaamyloid become damaged or destroyed, which then leads to the perikaryalloss of those locus ceruleus cells (Wallerian-like degeneration). Lossof locus ceruleus cells, and loss of the protective norepinephrine thatthey produce, triggers an increased release of pro-inflammatory cytokineand cytotoxic agents by microglial cells against decreasingly toleratedbeta amyloid aggregates. This results in further damage to, and loss of,locus ceruleus terminal fields and the norepinephrine that they produce,as well as damage to or loss of other nearby nerve cells. The result isa vicious cycle in which both the protective locus ceruleus cells andbeta amyloid-containing regions of the brain die. The present inventionbreaks this vicious cycle by using vagus nerve stimulation to induce therelease of larger quantities of norepinephrine from projections of apatient's locus ceruleus. Thus, maintaining norepinephrine release ashigh as possible may disrupt this degenerative cycle by reducingneuroinflammation, thereby halting or slowing the progression of thedisease and protecting the locus ceruleus itself.

The brain contains several neural networks that can be identified bybrain imaging. One such network, the default mode network (DMN), is theprincipal region within which AD-related pathologies occur. The locusceruleus is thought to project to all of the networks, including theDMN. Methods of the invention increase norepinephrine levels in the DMN,thereby reducing neuroinflammation there. Depending on the distributionof adrenergic receptor subtypes within the DMN, the vagus nervestimulation may also deactivate the DMN. The locus ceruleus projectsmost strongly to a network known as the ventral attention network (VAN).Activation of the VAN via the locus ceruleus also deactivates neuronalactivity in the DMN, which thereby reduces the pathological changes inthe DMN that accompany a high level of neuronal activity there.

The progression of AD can be monitored through the use of biomarkers. Apre-symptomatic phase occurs first, in which individuals are cognitivelynormal but some have AD pathological changes. This is followed by asecond prodromal phase of AD, commonly referred to as mild cognitiveimpairment (MCI). The final phase of AD is true dementia. Methods of theinvention may be applied to patients in any of these stages. For mostpatients, the stimulation may be performed for 30 minutes, and thetreatment is performed once a week for 12 weeks or longer, because theprogression of the disease from prodrome to true dementia is a chronicsituation. Alternatively, stimulation may be performed only whenpatients are attempting to learn important information. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the pathophysiology of patients. Differentstimulation parameters may also be selected as the course of thepatient's disease changes. In preferred embodiments, the disclosedmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

In one embodiment, the method of treatment includes positioning the coilof a magnetic stimulator non-invasively on or above a patient's neck andapplying a magnetically-induced electrical impulse non-invasively to thetarget region within the neck to stimulate, inhibit or otherwisemodulate selected nerve fibers that interact with the locus ceruleus. Inanother embodiment, surface electrodes are used to apply electricalimpulses non-invasively to the target region within the neck to likewisestimulate, inhibit or otherwise modulate selected nerve fibers thatinteract with the locus ceruleus. Preferably, the target region isadjacent to, or in close proximity with, the carotid sheath thatcontains the vagus nerve.

The non-invasive magnetic stimulator device is used to modulateelectrical activity of a vagus nerve, without actually introducing amagnetic field into the patient. The preferred stimulator comprises twotoroidal windings that lie side-by-side within separate stimulatorheads, wherein the toroidal windings are separated by electricallyinsulating material. Each toroid is in continuous contact with anelectrically conducting medium that extends from the patient's skin tothe toroid. The currents passing through the coils of the magneticstimulator will saturate its core (e.g., 0.1 to 2 Tesla magnetic fieldstrength for Supermendur core material). This will require approximately0.5 to 20 amperes of current being passed through each coil, typically 2amperes, with voltages across each coil of 10 to 100 volts. The currentis passed through the coils in bursts of pulses, as described below,shaping an elongated electrical field of effect.

In another embodiment of the invention, the stimulator comprises asource of electrical power and two or more remote electrodes that areconfigured to stimulate a deep nerve. The stimulator comprises twoelectrodes that lie side-by-side within a hand-held enclosure, whereinthe electrodes are separated by electrically insulating material. Eachelectrode is in continuous contact with an electrically conductingmedium that extends from the interface element of the stimulator to theelectrode. The interface element also contacts the patient's skin whenthe device is in operation.

Current passing through an electrode may be about 0 to 40 mA, withvoltage across the electrodes of about 0 to 30 volts. The current ispassed through the electrodes in bursts of pulses. There may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of about 20 to 1000 microseconds, preferably 200microseconds. A burst followed by a silent inter-burst interval repeatsat 1 to 5000 bursts per second (bps, similar to Hz), preferably at 15-50bps, and even more preferably at 25 bps. The preferred shape of eachpulse is a full sinusoidal wave.

A source of power supplies a pulse of electric charge to the electrodesor magnetic stimulator coil, such that the electrodes or magneticstimulator produce an electric current and/or an electric field withinthe patient. The electrical or magnetic stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of a nerve such as a vagus nerve, to cause the nerve todepolarize and reach a threshold for action potential propagation. Byway of example, the threshold electric field for stimulation of thenerve may be about 8 V/m at 1000 Hz. For example, the device may producean electric field within the patient of about 10 to 600 V/m (preferablyless than 100 V/m) and an electrical field gradient of greater than 2V/m/mm. Electric fields that are produced at the vagus nerve aregenerally sufficient to excite all myelinated A and B fibers, but notthe unmyelinated C fibers. However, by using a reduced amplitude ofstimulation, excitation of A-delta and B fibers may also be avoided.

The preferred stimulator shapes an elongated electric field of effectthat can be oriented parallel to a long nerve, such as a vagus. Byselecting a suitable waveform to stimulate the nerve, along withsuitable parameters such as current, voltage, pulse width, pulses perburst, inter-burst interval, etc., the stimulator produces acorrespondingly selective physiological response in an individualpatient. Such a suitable waveform and parameters are simultaneouslyselected to avoid substantially stimulating nerves and tissue other thanthe target nerve, particularly avoiding the stimulation of nerves thatproduce pain.

A cognitive fluctuation is a relatively abrupt change in the cognitivestatus of a dementia patient, which may be an hour-to-hour change or aday-to-day change. Treating or averting a cognitive fluctuation may beimplemented within the context of control theory. A controllercomprising, for example, one of the disclosed vagus nerve stimulators, aPID, and a feedforward model, provides input to the patient viastimulation of one or both of the patient's vagus nerves. Feedforwardmodels may be black box models, particularly models that make use ofsupport vector machines. Data for training and exercising the models arefrom noninvasive physiological and/or environmental signals obtainedfrom sensors located on or about the patient. The model predicts theonset of a cognitive fluctuation, which may be avoided prophylacticallythrough use of vagus nerve stimulation. If the cognitive fluctuation isin progress, the vagus nerve stimulation may terminate it.

The novel systems, devices and methods for treating dementia are morecompletely described in the following detailed description of theinvention, with reference to the drawings provided herewith, and inclaims appended hereto. Other aspects, features, advantages, etc. willbecome apparent to one skilled in the art when the description of theinvention herein is taken in conjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIGS. 1A-1B show that electrical stimulation of a vagus nerve in anormal patient (FIG. 1A) or Alzheimer patient (FIG. 1B) modulates theactivity of resting state networks in the patient's brain, particularlythe default mode network (DMN) and ventral attention network (VAN),through stimulation of the locus ceruleus via the nucleus tractussolitaris, such that norepinephrine is released into the networks.

FIGS. 2A-2E show a schematic view of nerve modulating devices accordingto the present invention, which supply controlled pulses of electricalcurrent to a magnetic stimulator coil (FIG. 2A) or to surface electrodes(FIG. 2B), and the figure also shows (FIGS. 2C, 2D, 2E) an exemplaryelectrical voltage/current profile and waveform for stimulating,blocking and/or modulating impulses that are applied to a nerve.

FIGS. 3A-3E illustrate a dual-toroid magnetic stimulator coil accordingto an embodiment of the present invention, which is shown to be situatedwithin a housing that contains electrically conducting material (FIGS.3A-3D), and it also shows the housing and cap of the dual-toroidmagnetic stimulator attached via cable to a box containing the device'simpulse generator, control unit, and power source (FIG. 3E).

FIGS. 4A-4D illustrate a dual-electrode stimulator according to anembodiment of the present invention, which is shown to house thestimulator's electrodes and electronic components (FIGS. 4A-4B), as wellas showing details of the head of the dual-electrode stimulator (FIGS.4C-4D).

FIGS. 5A-5D illustrate an alternate embodiment of the dual-electrodestimulator (FIGS. 5A-5C), also comparing it with an embodiment of themagnetic stimulator according to the present invention (FIG. 5D).

FIG. 6 illustrates the approximate position of the housing of thestimulator according one embodiment of the present invention, when usedto stimulate the right vagus nerve in the neck of a patient.

FIG. 7 illustrates the housing of the stimulator according oneembodiment of the present invention, when positioned to stimulate avagus nerve in the patient's neck, wherein the stimulator is applied tothe surface of the neck in the vicinity of the identified anatomicalstructures.

FIG. 8 illustrates connections between the controller and controlledsystem according to the present invention, their input and outputsignals, and external signals from the environment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In one embodiment, a time-varying magnetic field, originating andconfined to the outside of a patient, generates an electromagnetic fieldand/or induces eddy currents within tissue of the patient. In anotherembodiment, electrodes applied to the skin of the patient generatecurrents within the tissue of the patient. An objective of the inventionis to produce and apply electrical impulses that interact with thesignals of one or more nerves to achieve the therapeutic result ofaltering the course of dementia, particularly Alzheimer's disease. Muchof the disclosure will be directed specifically to treatment of apatient by electromagnetic stimulation in or around a vagus nerve, withdevices positioned non-invasively on or near a patient's neck. Inparticular, the present invention can be used to indirectly stimulate orotherwise modulate nerves that innervate the locus ceruleus. However, itwill be appreciated that the devices and methods of the presentinvention can be applied to other tissues and nerves of the body,including but not limited to other parasympathetic nerves, sympatheticnerves, spinal or cranial nerves. As recognized by those having skill inthe art, the methods should be carefully evaluated prior to use inpatients known to have preexisting cardiac issues.

Topics that are presented below in connection with the disclosure of theinvention include the following: (1) Overview of physiologicalmechanisms by which vagus nerve stimulation may modulate norepinephrinelevels by affecting the locus ceruleus, thereby altering the course ofAlzheimer's disease; (2) Description of Applicant's magnetic andelectrode-based nerve stimulating devices, describing in particular theelectrical waveform used to stimulate a vagus nerve; (3) Preferredembodiments of the magnetic stimulator; (4) Preferred embodiments of theelectrode-based stimulator; (5) Application of the stimulators to theneck of the patient; (6) Use of the devices with feedback andfeedforward to improve treatment of individual patients.

Overview of Physiological Mechanisms Through which the Disclosed VagusNerve Stimulation Methods May be Used to Treat Patients with Dementia

Alzheimer disease (AD) clinical decline and pathological processes occurgradually. AD is the end stage of many years of accumulation ofpathological changes, which begin to develop decades before the earliestclinical symptoms occur. A pre-symptomatic phase occurs first, in whichindividuals are cognitively normal but some have AD pathologicalchanges. This is followed by a second prodromal phase of AD, commonlyreferred to as mild cognitive impairment (MCI). The final phase of AD isdementia, defined as impairments that are severe enough to produce lossof function in learning and retaining newly acquired information(episodic declarative memory); in handling complex tasks and reasoningabilities (executive cognitive functions); in visuospatial ability andgeographic orientation; and in language functions [David S. KNOPMAN.Alzheimer's Disease and other dementias. Chapter 409 (pp. 2274-2283) In:Goldman's Cecil Medicine, 24th Edn. (Lee Goldman and Andrew I. Schafer,Eds.). Philadelphia: Elsevier-Saunders, 2012; MASDEU J C, Kreisl W C,Berman K F. The neurobiology of Alzheimer disease defined byneuroimaging. Curr Opin Neurol 25(4, 2012):410-420; Charles DeCARLI.Mild cognitive impairment: prevalence, prognosis, aetiology, andtreatment. Lancet Neurology 2(2003): 15-21; Richard MAYEUX. EarlyAlzheimer's Disease. N Engl J Med 362(2010): 2194-201; MUFSON E J,Binder L, Counts S E, DeKosky S T, de Toledo-Morrell L, Ginsberg S D,Ikonomovic M D, Perez S E, Scheff S W. Mild cognitive impairment:pathology and mechanisms. Acta Neuropathol 123(1, 2012):13-30].

Until recently, a definitive diagnosis of AD could only be made atautopsy or by brain biopsy of an individual, by identifying amyloidplaques and neurofibrillary tangles (NFTs) in the association regions ofthe individual's brain, particularly in the medial aspect of thetemporal lobe. The amyloid plaques are comprised of amyloids, and theneurofibrillary tangles are comprised of tau protein. The development ofamyloid plaques is necessary for the last of the hallmark AD-relatedlesions to develop, neuritic (senile) plaques, which are composed of acentral core of beta-amyloid peptides aggregated together with fibrilsof beta-amyloid, dystrophic neurites, reactive astrocytes, phagocyticcells, and other proteins and protein fragments derived fromdegenerating cells or liberated from neurons. Additional evidence of ADfrom an individual's autopsy or biopsy would include the presence of thefollowing: the granulovacuolar degeneration of Shimkowicz, the neuropilthreads of Braak, and neuronal loss with synaptic degeneration. Incontrast, dementia with Lewy bodies is characterized at autopsy by thepresence of Lewy bodies, which are lesions comprising clumps ofalpha-synuclein and ubiquitin, rather than clumps of beta-amyloid.

Amyloid precursor protein (APP) is a membrane protein that isconcentrated in the synapses of neurons. APP is the precursor moleculethat, upon proteolysis, generates ß-amyloid (Aß), the peptide that formsamyloid fibrils, which in turn become the primary component of theamyloid plaques found in the brains of AD patients. The lipid transportprotein apoE4 impairs Aß clearance and promotes Aß deposition,conferring an AD risk factor on individuals that carry apoE4.

Tau proteins, which are abundant in the central nervous system,stabilize microtubules. When tau proteins are defective and no longerstabilize microtubules properly, they can produce dementias, includingAD. Defective tau protein will aggregate and twist into neurofibrillarytangles (NFTs), so that the protein is no longer available thestabilization of microtubules. As a result, the neuronal cytoskeletonfalls apart, contributing to neuronal malfunction and cell death.

It is now thought that the earliest pathological evidence of Alzheimer'sdisease in humans (abnormally phosphorylated tau protein and pretanglematerial) appears most often in the locus ceruleus/subceruleus complex,which is a nucleus in the pons of the brainstem that is the principalsite for brain synthesis of norepinephrine (noradrenaline). Suchabnormal tau protein may appear in an individual before puberty or inearly young adulthood [Heiko BRAAK and Kelly Del Tredici. Thepathological process underlying Alzheimer's disease in individuals underthirty. Acta Neuropathol 121 (2011):171-181].

Despite the early involvement of the locus ceruleus in neurofibrillarytangle formation, a significant neuronal cell loss there may occur witha delay of 25 years, such that locus ceruleus cell loss in AD may be arelatively late but relatively rapid event [BUSCH C, Bohl J, Ohm T G.Spatial, temporal and numeric analysis of Alzheimer changes in thenucleus coeruleus. Neurobiol Aging 18(4, 1997):401-406; ZAROW C, LynessS A, Mortimer J A, Chui H C. Neuronal loss is greater in the locuscoeruleus than nucleus basalis and substantia nigra in Alzheimer andParkinson diseases. Arch Neurol 6(3, 2003):337-341; GRUDZIEN A, Shaw P,Weintraub S, Bigio E, Mash D C, Mesulam M M. Locus coeruleusneurofibrillary degeneration in aging, mild cognitive impairment andearly Alzheimer's disease. Neurobiol Aging 28(3, 2007):327-335; O'NEIL JN, Mouton P R, Tizabi Y, Ottinger M A, Lei D L, Ingram D K, Manaye K F.Catecholaminergic neuronal loss in locus coeruleus of aged female dtgAPP/PS1 mice. J Chem Neuroanat 34(3-4, 2007):102-107].

The mechanism of locus ceruleus cell loss is incompletely understood,but it appears to be a Wallerian-like degradation, in which damage tothe neurons and/or microvessels that are innervated by locus ceruleusaxons leads to death of the very same locus ceruleus cells that areinnervating those damaged neurons and/or microvessels [HAGLUND M,Sjöbeck M, Englund E. Locus ceruleus degeneration is ubiquitous inAlzheimer's disease: possible implications for diagnosis and treatment.Neuropathology 26(6, 2006):528-32]. Thus, the site of initial damage tothe locus ceruleus neuron appears to be its terminal field (e.g., nearthe senile plaque that it innervates), and perikaryal loss of the cellfollows as a secondary retrograde change. Evidence in support of thismechanism is that there is a correlation between locus ceruleusdegeneration and the density of plaques in regions of the cortex thatare innvervated by the locus ceruleus, and also that cortical-projectingneurons of the locus ceruleus degenerate selectively in AD [MARCYNIUK B,Mann D M, Yates P O. Loss of nerve cells from locus coeruleus inAlzheimer's disease is topographically arranged. Neurosci Lett 64(3,1986):247-52.; BONDAREFF W, Mountjoy C Q, Roth M. Loss of neurons oforigin of the adrenergic projection to cerebral cortex (nucleus locusceruleus) in senile dementia. Neurology 32(2, 1982):164-168; BONDAREFFW, Mountjoy C Q, Roth M, Rossor M N, Iversen L L, Reynolds G P, Hauser DL. Neuronal degeneration in locus ceruleus and cortical correlates ofAlzheimer disease. Alzheimer Dis Assoc Disord 1(4, 1987):256-62; GERMAND C, Manaye K F, White C L 3rd, Woodward D J, McIntire D D, Smith W K,Kalaria R N, Mann D M. Disease-specific patterns of locus coeruleus cellloss. Ann Neurol 32(5, 1992):667-76].

In AD rodent models, Aß first deposits in the olfactory bulb of thebrain, well before deposition in the brain structures that later developrich Aß deposits, with which impaired cognition is associated (thepiriform cortex, entorhinal cortex, and hippocampus) [WESSON D W, LevyE, Nixon R A, Wilson D A Olfactory dysfunction correlates withbeta-amyloid plaque burden in an Alzheimer's disease mouse model. JNeurosci 30(2010):505-514; WESSON D W, Borkowski A H, Landreth G E,Nixon R A, Levy E, Wilson D A. Sensory network dysfunction, behavioralimpairments, and their reversibility in an Alzheimer's ß-amyloidosismouse model. J Neurosci. 31(44, 2011):15962-15971]. The invariable andsevere involvement of the olfactory areas of the brain of human ADpatients also raises the possibility that the olfactory pathway may beinitially involved [PEARSON R C, Esiri M M, Hiorns R W, Wilcock G K,Powell T P. Anatomical correlates of the distribution of thepathological changes in the neocortex in Alzheimer disease. Proc NatlAcad Sci USA 82(13, 1985):4531-4534; FOSTER J, Sohrabi H, Verdile G,Martins R. Research criteria for the diagnosis of Alzheimer's disease:genetic risk factors, blood biomarkers and olfactory dysfunction. IntPsychogeriatr 20 (4, 2008):853-855; WILSON R S, Schneider J A, Arnold SE, Tang Y, Boyle P A, Bennett D A. Olfactory identification andincidence of mild cognitive impairment in older age. Arch Gen Psychiatry64(7, 2007):802-8; LI W, Howard J D, Gottfried J A. Disruption of odourquality coding in piriform cortex mediates olfactory deficits inAlzheimer's disease. Brain 133(9, 2010):2714-2726]. There is evidencethat a noradrenergic deficiency induces the olfactory cognitiveimpairments through an alteration of olfactory neurogenesis [GUERIN D,Sacquet J, Mandairon N, Jourdan F, Didier A. Early locus coeruleusdegeneration and olfactory dysfunctions in Tg2576 mice. Neurobiol Aging30(2, 2009):272-83].

After the initial tau and amyloid-related pathologies, the pathology ofAD patients' brains follows a course that allows for staging of thedisease. The distribution of plaques may differ considerably from thatof the neurofibrillary lesions, so staging of tau and amyloid-relatedpathologies are considered separately. Neurofibrillary tangles eitherantecede plaques or are formed independently. The tangles exhibit sixstages of development. In Stage I, specific projection cells in thetransentorhinal region are the first neurons to show the changes. It hasbeen suggested that this corresponds to AD progressing from its initialsite in the locus ceruleus to the transentorhinal region of the cerebralcortex, possibly via neuron-to-neuron transmission and transsynaptictransport of tau protein aggregates [Heiko BRAAK and Kelly Del Tredici.Alzheimer's pathogenesis: is there neuron-to-neuron propagation? ActaNeuropathol 121(2011):589-595; REY N L, Jardanhazi-Kurutz D, Terwel D,Kummer M P, Jourdan F, Didier A, Heneka M T. Locus coeruleusdegeneration exacerbates olfactory deficits in APP/PS1 transgenic mice.Neurobiol Aging. 33(2, 2012):426.e1-426.e11]. Consequently, a brainregion to which the earliest treatments of the present invention can bespecifically directed is the transentorhinal region of the cerebralcortex, which would be appropriate for individuals in early adulthood orpossibly even before puberty.

Stage II cases exhibit numerous transentorhinal NFTs and additional onesin the entorhinal region proper. Clinically, stage I and II cases arenot associated with intellectual decline (preclinical phase). Thepathologic process proceeds into both the hippocampal formation and thetemporal neocortex (stage III), and then reaches further associationareas of the basal neocortex (stage IV). The neurofibrinary pathologythen spreads superolaterally (stage V), eventually extending into theprimary areas of the neocortex (stage VI). The late stages V-VIrepresent fully developed AD.

Amyloid-deposition occurs in three stages (A-C). The initial patches areseen in the basal neocortex, most frequently in poorly myelinatedtemporal areas such as the perirhinal and/or ectorhinal fields (stageA). Some individuals develop initial deposits in young adulthood. Thedepositions increase in number and spread into the adjoining neocorticalareas and the hippocampal formation (stage B). Eventually, deposits arefound in all areas of the cortex, including the densely myelinatedprimary areas of the neocortex (stage C) [BRAAK H, Braak E.Neuropathological staging of Alzheimer-related changes. ActaNeuropathologica 82(1991): 239-259; BRAAK, H. and Braak, E. Staging ofAlzheimer's disease-related neurofibrillary changes. Neurobiol. Aging16(1995): 271-278; Heiko BRAAK, Eva Braak, Jiirgen Bohl and RalfReintjes. Age, neurofibrillary changes, Abeta-amyloid and the onset ofAlzheimer's disease. Neuroseience letters 210 (1996): 87-90; BRAAK, H.and Braak, E. Frequency of Stages of Alzheimer-Related Lesions inDifferent Age Categories. Neurobiology of Aging 18(4, 1997): 351-357;HYMAN B T, Gomez-Isla T. The natural history of Alzheimerneurofibrillary tangles and amyloid deposits. Neurobiol Aging 18(4,1997):386-387; Barbel SCHONHEIT, Rosemarie Zarski, Thomas G. Ohm.Spatial and temporal relationships between plaques and tangles inAlzheimer-pathology. Neurobiology of Aging 25 (2004): 697-711].

Symptoms of dementia are caused by dysfunction in portions of the brainthat are responsible for memory, reasoning, spatial orientation, andlanguage. The anatomical location of lesions in neurodegenerativediseases are not diffuse, random, or confluent, but are instead locatedin specific large-scale distributed networks. Thus, pathological changesin Alzheimer disease affect regions of the brain that are interconnectedby well-defined groups of connections, and the disease process mayextend along the interconnected nerve fibers. Maps of Aß plaquelocations can now be made noninvasively in living individuals using PETimaging [KLUNK, W. E., Engler, H., Nordberg, A., Wang, Y., Blomqvist,G., et al. Imaging brain amyloid in Alzheimer's disease with PittsburghCompound-B. Ann. Neurol., 55(2004), 306-319]. Such images of Aß plaquestaken at the earliest stages of AD show a distribution that isremarkably similar to the anatomy of what is known as the defaultnetwork [BUCKNER, R. L., Snyder, A. Z., Shannon, B. J., LaRossa, G.,Sachs, R., et al. Molecular, structural, and functional characterizationof Alzheimer's disease: evidence for a relationship between defaultactivity, amyloid, and memory. J. Neurosci. 25(2005):7709-7717; BUCKNERR L, Andrews-Hanna J R, Schacter D L. The brain's default network:anatomy, function, and relevance to disease. Ann NY Acad Sci1124(2008):1-38]. The default network includes the posterior cingulate,medial prefronta and bilateral inferior parietal cortices, and medialtemporal lobe structures. Thus, specific brain regions that are activein the default network in young adults show amyloid deposition in olderadults with AD. Consequently, a brain region to which treatments of thepresent invention can be specifically directed is the default network.The default network (and other so-called resting state networks) will bediscussed below, after first summarizing what is known about the rolesof A

plaques and A

oligomers in AD pathogenesis.

Until recently, it was generally agreed that AD begins when cellsabnormally process the amyloid precursor protein (APP), which then leadsto excess production or reduced clearance of

-amyloid (A

) in the patient's cortex. Excess of one or more forms of A

leads to a cascade, characterized by abnormal tau protein aggregation,synaptic dysfunction, cell death, and brain shrinkage. It is thoughtthat extracellular deposits of A

in the brains of AD patients promote tau polymerization in the vicinityof the deposits, leading to the neuritic plaques. Additionally, a rolein the pathogenesis of AD and other neurodegenerative diseases has beenvariously assigned to many factors that are known to be capable ofdamaging postmitotic cells, such as greater oxidative stress,mitochondrial dysfunction, chronic inflammation, and/or failure of theubiquitin-proteasome system [John HARDY and Dennis J. Selkoe. Theamyloid hypothesis of Alzheimer's disease: progress and problems on theroad to therapeutics. Science 297(2002): 353-356].

Despite the ability of the amyloid cascade hypothesis to organize muchof what is known about the biochemistry and genetics of AD, thehypothesis provides an incomplete or unsatisfactory description of ADpathogenesis, for at least the following reasons. Plaques are found incognitively normal individuals, and plaque burden does not correlatewith memory decline. Removal of amyloid plaques by immunotherapy failsto improve cognition. Some forms of A

may actually be protective, rather than toxic. Injection of synthetic A

preparations fails to induce spreading of AD-related lesions. Theamyloid cascade hypothesis also does not explain why certain populationsof neurons are selectively vulnerable to neuronal death while othersremain resistant. The absence of A

deposition in young individuals with abnormally phosphorylated tauprotein (pretangle material) is not compatible with the amyloid cascadehypothesis, which assumes that A

drives AD pathogenesis and only secondarily induces intraneuronal tauchanges [Christian HAASS. Initiation and propagation ofneurodegeneration. Nature Medicine 16(11, 2010): 1201-1204; Heiko BRAAKand Kelly Del Tredici. The pathological process underlying Alzheimer'sdisease in individuals under thirty. Acta Neuropathol 121(2011):171-181; CASTELLANI RJ, Lee H G, Siedlak S L, Nunomura A, HayashiT, Nakamura M, Zhu X, Perry G, Smith M A. Reexamining Alzheimer'sdisease: evidence for a protective role for amyloid-beta proteinprecursor and amyloid-beta. J Alzheimers Dis. 2009; 18(2):447-52;Siddhartha MONDRAGON-RODRIGUEZ, George Perry, Xiongwei Zhu, and JannicBoehm. Amyloid beta and tau proteins as therapeutic targets forAlzheimer's disease treatment: rethinking the current strategy. Int JAlzheimers Dis. (2012); 2012: 630182, pp. 1-7].

Therefore, variants of the amyloid cascade hypothesis of AD pathogenesishave also been proposed. The revised models shift from the initial focuson amyloid plaques to the newer concept that AD memory failure is causedby small soluble oligomers of the Aß peptide, toxins that target anddisrupt particular synapses. According to this view, high concentrationsof pathogenic Aß and its oligomers reduce glutamatergic transmission,inhibit long-term potentiation and facilitate long-term depression, andthey induce synapse loss and its associated cognitive impairment. Thus,theories of AD pathogenesis have shifted from Aß plaques to the effectsof Aß oligomers on synapses [Rudolph E TANZI. The synaptic Aß hypothesisof Alzheimer disease. Nature Neuroscience 8 (8, 2005): 977-979; Dennis JSELKOE. The ups and downs of Aß. Nature Medicine 12(7, 2006): 758-759;FERREIRA ST, Klein W L. The Aß oligomer hypothesis for synapse failureand memory loss in Alzheimer's disease. Neurobiol Learn Mem 96(4,2011):529-43; KOFFIE R M, Hyman B T, Spires-Jones T L. Alzheimer'sdisease: synapses gone cold. Mol Neurodegener 6(1, 2011):63, pp. 1-9;SHENG M, Sabatini B L, Südhof T C. Synapses and Alzheimer's disease.Cold Spring Harb Perspect Biol 4(5, 2012). pii: a005777, pp. 1-18].

Synaptically connected neurons form neural networks. Thus, an extensionof synaptic dysfunction models of AD considers the effects of thosesynaptic dysfunctions on entire neural networks. At the network level,high concentrations of pathogenic Aß and its oligomers causedysrhythmias, including neuronal synchronization, epileptiform activity,seizures, and postictal suppression [DAMELIO M, Rossini P M. Brainexcitability and connectivity of neuronal assemblies in Alzheimer'sdisease: From animal models to human findings. Prog Neurobiol 99(1,2012):42-60; GEULA C. Abnormalities of neural circuitry in Alzheimer'sdisease: hippocampus and cortical cholinergic innervation. Neurology51(1 Suppl 1, 1998):518-29; GLEICHMANN M, Mattson M P. Alzheimer'sdisease and neuronal network activity. Neuromolecular Med 12(1,2010):44-7; PALOP J J, Chin J, Mucke L. A network dysfunctionperspective on neurodegenerative diseases. Nature 443(7113,2006):768-773; PALOP J J, Mucke L. Synaptic depression and aberrantexcitatory network activity in Alzheimer's disease: two faces of thesame coin? Neuromolecular Med 12(1, 2010):48-55; Jorge J. PALOP andLennart Mucke. Amyloid-ß Induced Neuronal Dysfunction in Alzheimer'sDisease: From Synapses toward Neural Networks. Nat Neurosci 13(7, 2010):812-818; SAVIOZ A, Leuba G, Vallet P G, Walzer C. Contribution of neuralnetworks to Alzheimer disease's progression. Brain Res Bull 80(4-5,2009):309-314; SEELEY W W, Crawford R K, Zhou J, Miller B L, Greicius MD. Neurodegenerative diseases target large-scale human brain networks.Neuron 62(1, 2009):42-52; SMALL D H. Network dysfunction in Alzheimer'sdisease: does synaptic scaling drive disease progression? Trends Mol Med14(3, 2008):103-108; VERRET L, Mann E O, Hang G B, Barth A M, Cobos I,Ho K, Devidze N, Masliah E, Kreitzer A C, Mody I, Mucke L, Palop J J.Inhibitory interneuron deficit links altered network activity andcognitive dysfunction in Alzheimer model. Cell 149(3, 2012):708-721].

The manner in which AD may be spread between interconnected neuronswithin networks is not known, but several mechanisms have beensuggested. First, early lesions within key synaptic convergence zonesmay disconnect or weaken functional circuits, thereby inducingdeleterious network-wide compensations, leading to progressivedegeneration within the circuit. Second, retrograde axonal transportdeficits may cut off growth factor supply to long-range projectionneurons, resulting in axonal degeneration, synapse loss, andpost-synaptic dendrite retraction. Third, as seen in prion disease,misfolded disease proteins may themselves propagate along neuralprocesses, then move throughout local and then long-range circuits viatranssynaptic spread. Fourth, the network may exhibit some property,such as having an unusually high metabolic rate and/or being incessantlybusy, that predisposes cells in the network to forming lesions or to theinability to repair lesions. These potential network degenerationmechanisms are not mutually exclusive.

Activation of a neural network is accompanied by oscillations within thenetwork. Low frequency oscillations are likely associated withconnectivity at the largest scale of the network, while higherfrequencies are exhibited by smaller sub-networks within the largernetwork, which may be modulated by activity in the slower oscillatinglarger network. The default network, also called the default modenetwork (DMN), default state network, or task-negative network (TNN), isone such network that is characterized by coherent neuronal oscillationsat a rate lower than 0.1 Hz. Other large scale networks also have thisslow-wave property, but the default network is particularly relevant tothe pathogenesis of AD because A

deposits form preferentially within it. Aß deposits form within the DMNas individuals age, whether or not the individuals have dementia[BUCKNER, R. L., Snyder, A. Z., Shannon, B. J., LaRossa, G., Sachs, R.,et al. Molecular, structural, and functional characterization ofAlzheimer's disease: evidence for a relationship between defaultactivity, amyloid, and memory. J. Neurosci. 25(2005):7709-7717; BUCKNERR L, Andrews-Hanna J R, Schacter D L. The brain's default network:anatomy, function, and relevance to disease. Ann N Y Acad Sci1124(2008):1-38; SPERLING R A, Laviolette P S, O'Keefe K, O'Brien J,Rentz D M, Pihlajamaki M, Marshall G, Hyman B T, Selkoe D J, Hedden T,Buckner R L, Becker J A, Johnson K A. Amyloid deposition is associatedwith impaired default network function in older persons withoutdementia. Neuron 63(2, 2009):178-188; DAMOISEAUX J S, Beckmann C F,Arigita E J, Barkhof F, Scheltens P, Stam C J, Smith S M, Rombouts S A.Reduced resting-state brain activity in the “default network” in normalaging. Cereb Cortex 18(8, 2008):1856-64; PALVA J M, Palva S. Infra-slowfluctuations in electrophysiological recordings,blood-oxygenation-level-dependent signals, and psychophysical timeseries. Neuroimage 62(4, 2012):2201-2211; STEYN_ROSS M L, Steyn-Ross DA, Sleigh J W, Wilson M T. A mechanism for ultra-slow oscillations inthe cortical default network. Bull Math Biol 73(2, 2011):398-416].

As the AD progresses, the DMN itself undergoes pathological changesinternally and in terms of its connections to other slow-wave networks[GREICIUS M D, Srivastava G, Reiss A L, Menon V. Default-mode networkactivity distinguishes Alzheimer's disease from healthy aging: evidencefrom functional MRI. Proc Natl Acad Sci USA 101(13, 2004):4637-4642;MEVEL K, Chételat G, Eustache F, Desgranges B. The default mode networkin healthy aging and Alzheimer's disease. Int J Alzheimers Dis. 2011;2011:535816. Epub 2011 Jun. 14, pp. 1-9; SORG C, Riedl V, Mühlau M,Calhoun V D, Eichele T, Läer L, Drzezga A, Förstl H, Kurz A, Zimmer C,Wohlschläger A M. Selective changes of resting-state networks inindividuals at risk for Alzheimer's disease. Proc Natl Acad Sci USA104(47, 2007):18760-18765; LI R, Wu X, Chen K, Fleisher A S, Reiman E M,Yao L. Alterations of Directional Connectivity among Resting-StateNetworks in Alzheimer Disease. AJNR Am J Neuroradiol. 2012 Jul. 12.(Epub ahead of print, pp. 1-6); BRIER M R, Thomas J B, Snyder A Z,Benzinger T L, Zhang D, Raichle M E, Holtzman D M, Morris J C, Ances BM. Loss of intranetwork and internetwork resting state functionalconnections with Alzheimer's disease progression. J Neurosci 32(26,2012):8890-9].

The default mode network corresponds to task-independent introspection(e.g., daydreaming), or self-referential thought. When the DMN isactivated, the individual is ordinarily awake and alert, but the DMN mayalso be active during the early stages of sleep and during conscioussedation. The posterior cingulate cortex (PCC) and adjacent precuneusand the medial prefrontal cortex (mPFC) are the two most clearlydelineated regions within the DMN. One reason that amyloid plaques formpreferentially in the DMN may be that it is activated by default, whenthe brain is not otherwise engaged in specific tasks, and it istherefore on average more metabolically active than other such networks.Similarly, the DMN is vulnerable to developing Aß deposition andAlzheimer disease pathology because, averaged over the course of alifetime, it is the most synaptically active area of the brain, with themost cortical hubs. Thus, according to the synaptic A

hypothesis of Alzheimer disease, the A

deposits will form preferentially in the vicinity of those activesynapses. A corollary of this line of reasoning is that education andother cognitive activity is protective against Alzheimer disease becauseit results in less activity, on average over a lifetime, within the DMN[RAICHLE M E, Snyder A Z. A default mode of brain function: a briefhistory of an evolving idea. Neuroimage 37(4, 2007):1083-1090; BROYD SJ, Demanuele C, Debener S, Helps S K, James C J, Sonuga-Barke E J.Default-mode brain dysfunction in mental disorders: a systematic review.Neurosci Biobehav Rev 33(3, 2009):279-96; BUCKNER R L, Andrews-Hanna JR, Schacter D L. The brain's default network: anatomy, function, andrelevance to disease. Ann N Y Acad Sci 1124(2008):1-38; BUCKNER R L,Sepulcre J, Talukdar T, Krienen F M, Liu H, Hedden T, Andrews-Hanna J R,Sperling R A, Johnson K A. Cortical hubs revealed by intrinsicfunctional connectivity: mapping, assessment of stability, and relationto Alzheimer's disease. J Neurosci 29(2009):1860-1873; GREICIUS M D,Krasnow B, Reiss A L, Menon V. Functional connectivity in the restingbrain: a network analysis of the default mode hypothesis. Proc Natl AcadSci USA 100(2003): 253-258].

During goal-oriented activity, the DMN is deactivated and one or more ofseveral other networks, so-called task-positive networks (TPN), areactivated. DMN activity is attenuated rather than extinguished duringthe transition between states, and is observed, albeit at lower levels,alongside task-specific activations. Strength of the DMN deactivationappears to be inversely related to the extent to which the task isdemanding. Thus, DMN has been described as a task-negative network,given the apparent antagonism between its activation and taskperformance. Patients with AD appear to have problems deactivating theirDMN [ROMBOUTS SA, Barkhof F, Goekoop R, Stam C J, Scheltens P. Alteredresting state networks in mild cognitive impairment and mild Alzheimer'sdisease: an fMRI study. Hum Brain Mapp 26(4, 2005):231-239; WERMKE M,Sorg C, Wohlschlager A M, Drzezga A. A new integrative model of cerebralactivation, deactivation and default mode function in Alzheimer'sdisease. Eur J Nucl Med Mol Imaging 35 (Suppl 1, 2008):512-524].

The term low frequency resting state networks (LFRSN or simply RSN) isused to describe both the task-positive and task-negative networks.Using independent component analysis (ICA) and related methods to assesscoherence of fMRI Blood Oxygenation Level Dependent Imaging (BOLD)signals in terms of temporal and spatial variation, as well asvariations between individuals, low frequency resting state networks inaddition to the DMN have been identified, corresponding to differenttasks. They are related to their underlying anatomical connectivity andreplay at rest the patterns of functional activation evoked by thebehavioral tasks. That is to say, brain regions that are commonlyrecruited during a task are anatomically connected and maintain in theresting state (in the absence of any stimulation) a significant degreeof temporal coherence in their spontaneous activity, which is whatallows them to be identified at rest [SMITH SM, Fox P T, Miller K L,Glahn D C, Fox P M, et al. Correspondence of the brain's functionalarchitecture during activation and rest. Proc Natl Acad Sci USA106(2009): 13040-13045].

Frequently reported resting state networks (RSNs), in addition to theDMN, include the sensorimotor RSN, the executive control RSN, up tothree visual RSNs, two lateralized fronto-parietal RSNs, the auditoryRSN and the temporo-parietal RSN. However, different investigators usedifferent methods to identify the low frequency resting state networks,so different numbers and somewhat different identities of RSNs arereported by different investigators [COLE DM, Smith S M, Beckmann C F.Advances and pitfalls in the analysis and interpretation ofresting-state FMRI data. Front Syst Neurosci 4(2010):8, pp. 1-15].Examples of RSNs are described in publications cited by COLE and thefollowing: ROSAZZA C, Minati L. Resting-state brain networks: literaturereview and clinical applications. Neurol Sci 32(5, 2011):773-85; ZHANGD, Raichle M E. Disease and the brain's dark energy. Nat Rev Neurol 6(1,2010):15-28; DAMOISEAUX, J. S., Rombouts, S. A. R. B., Barkhof, F.,Scheltens, P., Stam, C. J., Smith, S. M., Beckmann, C. F. Consistentresting-state networks across healthy subjects. Proc. Natl. Acad. Sci.U.S.A. 103(2006): 13848-13853 FOX M D, Snyder A Z, Vincent J L, CorbettaM, Van Essen D C, Raichle M E. The human brain is intrinsicallyorganized into dynamic, anticorrelated functional networks. Proc NatlAcad Sci USA 102(2005):9673-9678].

For purposes of discussion, we adopt the set of resting state networksidentified by L I et al, with the understanding that according to theabove-cited publications, a more or less detailed set could also beadopted [LI R, Wu X, Chen K, Fleisher A S, Reiman E M, Yao L.Alterations of Directional Connectivity among Resting-State Networks inAlzheimer Disease. AJNR Am J Neuroradiol. 2012 Jul. 12. [Epub ahead ofprint, pp. 1-6]. The resting state networks are shown in FIG. 1 for bothnormal individuals (FIG. 1A) and for individuals with advancedAlzheimer's disease (FIG. 1B). Also shown there are the connectionsbetween the networks, with the larger arrows indicating strongerconnections. Solid and dashed arrows are, respectively, for positive andnegative connections.

The resting state networks shown in FIG. 1 are as follows. Thedefault-mode network (DMN) includes the posterior cingulate, medialprefronta and bilateral inferior parietal cortices, and the medialtemporal lobe structures. The self-referential network (SRN) includesregions from the medial-ventral prefrontal cortex, the anteriorcingulate, and the posterior cingulate. Previous investigators includedthe SRN in the DMN. As described above, the DMN is the principal site inwhich amyloid plaques and other pathologies related to AD occur.

The dorsal attention network (DAN) and ventral attention network (VAN)are two networks responsible for attentional processing. The VAN isinvolved in involuntary actions and exhibits increased activity upondetection of salient targets, especially when they appear in unexpectedlocations (bottom-up activity, e.g. when an automobile driverunexpectedly senses a hazard). The DAN is involved in voluntary(top-down) orienting and increases activity after presentation of cuesindicating where, when, or to what individuals should direct theirattention [FOX M D, Corbetta M, Snyder A Z, Vincent J L, Raichle M E.Spontaneous neuronal activity distinguishes human dorsal and ventralattention systems. Proc Natl Acad Sci USA 103(2006):10046-10051; WEN X,Yao L, Liu Y, Ding M. Causal interactions in attention networks predictbehavioral performance. J Neurosci 32(4, 2012):1284-1292]. The DAN isbilaterally centered in the intraparietal sulcus and the frontal eyefield. The VAN is largely right lateralized in the temporal-parietaljunction and the ventral frontal cortex.

The lateral visual network (LVN) and medial visual network (MVN) are twonetworks for visual processing and are respectively located in thelateral and medial parts of the visual cortex. The auditory network (AN)is responsible for auditory processing and is located in the bilateralsuperior temporal gyrus and in the primary and secondary auditorycortices. The sensory-motor network (SMN) is the network covering thesomatosensory, premotor, and supplementary motor cortices. The LVN, MVN,AN, and SMN are four networks related to sensory processing, and theDMN, SRN, DAN, and VAN are associated with higher cognitive function.

The present invention modulates the activity of these resting statenetworks via the locus ceruleus by electrically stimulating the vagusnerve, as shown in FIG. 1. Stimulation of a network by that route mayactivate or deactivate a network, depending on the detailedconfiguration of adrenergic receptor subtypes within the network andtheir roles in enhancing or depressing neural activity within thenetwork, as well as subsequent network-to-network interactions.According to the invention, preferential stimulation of a particularnetwork, such as the DMN, may be accomplished by providing a vagus nervestimulation signal that entrains to the signature EEG pattern of thatnetwork (see below and MANTINI D, Perrucci M G, Del Gratta C, Romani GL, Corbetta M. Electrophysiological signatures of resting state networksin the human brain. Proc Natl Acad Sci USA 104(32, 2007):13170-13175).By this method, it may be possible to preferentially attenuate ordeactivate the DMN which, as described above, will decrease theprogression of AD by reducing its metabolic activity and reduce thenumber of its synapses that are active in generating A

pathologies. Activation of another network such as the VAN may alsoproduce the same effect, via network-to-network interactions. Anotherway that the stimulation resists AD pathogenesis is to increase theavailability of norepinephrine in the DMN via the locus ceruleus which,as described below, counteracts the intense inflammation that occurs inthe vicintiy of A

-rich synapses. On a more global level, the reduced progression of AD bythese mechanisms will also delay toxic effects in the terminal fields oflocus ceruleus axons, thereby protecting the locus ceruleus fromdegradation and allowing it to continue counteracting the inflammation.Thus, although previous investigators have disclosed effects of vagusnerve stimulation on the hippocampus, which is altered in AD, thepresent invention goes far beyond that in disclosing the use of vagusnerve stimulation to affect whole resting state neworks, includingeffects that one resting state network has on another resting statenetwork. It also uses that stimulation in an effort to slow or stopprogression of the AD, not simply treat cognitive symptoms of AD[SANCHEZ MM, Moghadam S, Naik P, Martin K J, Salehi A. Hippocampalnetwork alterations in Alzheimer's disease and Down syndrome: fromstructure to therapy. J Alzheimers Dis. 2011; 26 Suppl 3:29-47; SHEN H,Fuchino Y, Miyamoto D, Nomura H, Matsuki N. Vagus nerve stimulationenhances perforant path-CA3 synaptic transmission via the activation ofß-adrenergic receptors and the locus coeruleus. Int JNeuropsychopharmacol 15(4, 2012):523-30].

A vagus nerve is composed of motor and sensory fibers. The vagus nerveleaves the cranium and is contained in the same sheath of dura matterwith the accessory nerve. The vagus nerve passes down the neck withinthe carotid sheath to the root of the neck. The branches of distributionof the vagus nerve include, among others, the superior cardiac, theinferior cardiac, the anterior bronchial and the posterior bronchialbranches. On the right side, the vagus nerve descends by the trachea tothe back of the root of the lung, where it spreads out in the posteriorpulmonary plexus. On the left side, the vagus nerve enters the thorax,crosses the left side of the arch of the aorta, and descends behind theroot of the left lung, forming the posterior pulmonary plexus.

A vagus nerve in man consists of over 100,000 nerve fibers (axons),mostly organized into groups. The groups are contained within fasciclesof varying sizes, which branch and converge along the nerve. Undernormal physiological conditions, each fiber conducts electrical impulsesonly in one direction, which is defined to be the orthodromic direction,and which is opposite the antidromic direction. However, externalelectrical stimulation of the nerve may produce action potentials thatpropagate in orthodromic and antidromic directions. Besides efferentoutput fibers that convey signals to the various organs in the body fromthe central nervous system, the vagus nerve conveys sensory (afferent)information about the state of the body's organs back to the centralnervous system. Some 80-90% of the nerve fibers in the vagus nerve areafferent (sensory) nerves communicating the state of the viscera to thecentral nervous system.

The vagus (or vagal) afferent nerve fibers arise from cell bodieslocated in the vagal sensory ganglia. These ganglia take the form ofswellings found in the cervical aspect of the vagus nerve just caudal tothe skull. There are two such ganglia, termed the inferior and superiorvagal ganglia. They are also called the nodose and jugular ganglia,respectively (See FIG. 1). The jugular (superior) ganglion is a smallganglion on the vagus nerve just as it passes through the jugularforamen at the base of the skull. The nodose (inferior) ganglion is aganglion on the vagus nerve located in the height of the transverseprocess of the first cervical vertebra. Vagal afferents traverse thebrainstem in the solitary tract, with some eighty percent of theterminating synapses being located in the nucleus of the tractussolitarius (or nucleus tractus solitarii, or NTS). The NTS projects to awide variety of structures in the central nervous system, such as theamygdala, raphe nuclei, periaqueductal gray, nucleusparagigantocellurlais, olfactory tubercule, locus ceruleus, nucleusambiguus and the hypothalamus. The NTS also projects to the parabrachialnucleus, which in turn projects to the hypothalamus, the thalamus, theamygdala, the anterior insular, and infralimbic cortex, lateralprefrontal cortex, and other cortical regions [JEAN A. The nucleustractus solitarius: neuroanatomic, neurochemical and functional aspects.Arch Int Physiol Biochim Biophys 99(5, 1991): A3-A52].

With regard to vagal efferent nerve fibers, two vagal components haveevolved in the brainstem to regulate peripheral parasympatheticfunctions. The dorsal vagal complex, consisting of the dorsal motornucleus and its connections, controls parasympathetic function primarilybelow the level of the diaphragm, while the ventral vagal complex,comprised of nucleus ambiguus and nucleus retrofacial, controlsfunctions primarily above the diaphragm in organs such as the heart,thymus and lungs, as well as other glands and tissues of the neck andupper chest, and specialized muscles such as those of the esophagealcomplex. For example, the cell bodies for the preganglionicparasympathetic vagal neurons that innervate the heart reside in thenucleus ambiguus.

The locus ceruleus is also shown in FIG. 1. The vagus nerve transmitsinformation to the locus ceruleus via the nucleus tractus solitarius(NTS), which has a direct projection to the dendritic region of thelocus ceruleus. Other afferents to, and efferents from, the locusceruleus are described by SARA et al, SAMUELS et al, andASTON-JONES—SARA S J, Bouret S. Orienting and Reorienting: The LocusCoeruleus Mediates Cognition through Arousal. Neuron 76(1, 2012):130-41;SAMUELS E R, Szabadi E. Functional neuroanatomy of the noradrenergiclocus coeruleus: its roles in the regulation of arousal and autonomicfunction part I: principles of functional organisation. CurrNeuropharmacol 6(3):235-53; SAMUELS, E. R., and Szabadi, E. Functionalneuroanatomy of the noradrenergic locus coeruleus: its roles in theregulation of arousal and autonomic function part II: physiological andpharmacological manipulations and pathological alterations of locuscoeruleus activity in humans. Curr. Neuropharmacol. 6(2008), 254-285;Gary ASTON-JONES. Norepinephrine. Chapter 4 (pp. 47-57) in:Neuropsychopharmacology: The Fifth Generation of Progress (Kenneth L.Davis, Dennis Charney, Joseph T. Coyle, Charles Nemeroff, eds.)Philadelphia: Lippincott Williams & Wilkins, 2002].

In addition to the NTS, the locus ceruleus receives input from thenucleus gigantocellularis and its neighboring nucleusparagigantocellularis, the prepositus hypoglossal nucleus, theparaventricular nucleus of the hypothalamus, Barrington's nucleus, thecentral nucleus of the amygdala, and prefrontal areas of the cortex.These same nuclei may receive input from the NTS, such that stimulationof the vagus nerve may modulate the locus ceruleus via the NTS and thenvia a subsequent relay through these structures. In FIG. 1, thesestructures are labelled collectively as “Relay Nuclei.”

The locus ceruleus has widespread projections throughout the cortex andis presumed to project to each of the resting state networks shown inFIG. 1, as indicated by arrows from the locus ceruleus to those networks[SAMUELS E R, Szabadi E. Functional neuroanatomy of the noradrenergiclocus coeruleus: its roles in the regulation of arousal and autonomicfunction part I: principles of functional organisation. CurrNeuropharmacol 6 (3):235-53]. It also projects to subcortical regions,notably the raphe nuclei, which release serotonin to the rest of thebrain, including the resting state networks shown in FIG. 1. Anincreased dorsal raphe nucleus firing rate is thought to be secondary toan initial increased locus ceruleus firing rate from vagus nervestimulation [Adrienne E. DORR and Guy Debonnelv. Effect of vagus nervestimulation on serotonergic and noradrenergic transmission. J PharmacolExp Ther 318(2, 2006):890-898; MANTA S, Dong J, Debonnel G, Blier P.Enhancement of the function of rat serotonin and norepinephrine neuronsby sustained vagus nerve stimulation. J Psychiatry Neurosci 34(4,2009):272-80]. In AD, extensive serotonergic denervation occurs, andreduced serotonin in the cortex is likely due to loss of projectionsfrom the raphe nuclei. As with the locus ceruleus, the raphe nuclei area site of neurofibrillatory tangles and neuron loss. Consequently,stimulation of the raphe nuclei, either via the nucleus tractussolitarius or via the locus ceruleus may inhibit degradation of theraphe nuclei. Protection of the locus ceruleus would accordingly alsoprotect the raphe nuclei. This may be of significance particularly as itrelates to the neuropsychiatric aspects of AD [FRANCIS P T, Ramirez M J,Lai M K. Neurochemical basis for symptomatic treatment of Alzheimer'sdisease. Neuropharmacology 59(4-5, 2010):221-229].

The locus ceruleus also has projections to autonomic nuclei, includingthe dorsal motor nucleus of the vagus, as shown in FIG. 1 [FUKUDA, A.,Minami, T., Nabekura, J., Oomura, Y. The effects of noradrenaline onneurones in the rat dorsal motor nucleus of the vagus, in vitro. J.Physiol., 393 (1987): 213-231; MARTINEZ-PENA y Valenzuela, I., Rogers,R. C., Hermann, G. E., Travagli, R. A. (2004) Norepinephrine effects onidentified neurons of the rat dorsal motor nucleus of the vagus. Am. J.Physiol. Gas-trointest. Liver Physiol., 286, G333-G339; TERHORST, G. J.,Toes, G. J., Van Willigen, J. D. Locus coeruleus projections to thedorsal motor vagus nucleus in the rat. Neuroscience, 45(1991): 153-160].

Although the locus ceruleus is presumed to project to all of the restingnetworks shown in FIG. 1, it is thought to project most strongly to theventral attention network (VAN), which is indicated by a thicker arrowthan the arrows to the other networks [CORBETTA M, Patel G, Shulman G L.The reorienting system of the human brain: from environment to theory ofmind. Neuron 58(3, 2008):306-24; MANTINI D, Corbetta M, Perrucci M G,Romani G L, Del Gratta C. Large-scale brain networks account forsustained and transient activity during target detection. Neuroimage44(1, 2009):265-274]. The attention systems (VAN and DAN) have beeninvestigated long before their identification as resting state networks,and functions attributed to the VAN have in the past been attributed tothe locus ceruleus/noradrenaline system [ASTON-JONES G, Cohen J D. Anintegrative theory of locus coeruleus-norepinephrine function: adaptivegain and optimal performance. Annu Rev Neurosci 28(2005):403-50; BOURETS, Sara S J. Network reset: a simplified overarching theory of locuscoeruleus noradrenaline function. Trends Neurosci 28(11, 2005):574-82;SARA S J, Bouret S. Orienting and Reorienting: The Locus CoeruleusMediates Cognition through Arousal. Neuron 76(1, 2012):130-41; PETERSENS E, Posner M I. The attention system of the human brain: 20 yearsafter. Annu Rev Neurosci 35(2012):73-89; BERRIDGE C W, Waterhouse B D.The locus coeruleus-noradrenergic system: modulation of behavioral stateand state-dependent cognitive processes. Brain Res Brain Res Rev 42(1,2003):33-84].

Locus ceruleus neurons exhibit both tonic and phasic activity modes.Tonic activity is low in an unaroused state that facilitates sleep anddisengagement from the environment, moderate when the individual isengaged in a focused task of high utility and filtering out irrelevantstimuli, and high when the organism is not committed to a task but isresponsive to unanticipated changes in the environment. Individuals withlow tonic activity are not alert, and individuals with high tonicactivity are easily distracted and anxious. The second component oflocus ceruleus discharge is the phasic response to stimuli. The phasicsignal may be understood to be an “interrupt” signal that allows theflexible configuration of a target network once a target is detected,which is to say, a reorienting from one task state to another. Whenutility of the phasic activity relative to in the task wanes, locusceruleus neurons revert to a tonic activity mode, which would oftencorrespond to either the low-tone unaroused state or the high-tonedistractable state.

Many processes in addition to those that produce of A

oligomers at synapses contribute to the pathology of AD [QUERFURTH H W,LaFerla F M. Alzheimer's disease. N Engl J Med 362(4, 2010):329-44;ZLOKOVIC B V. Neurovascular pathways to neurodegeneration in Alzheimer'sdisease and other disorders. Nat Rev Neurosci 12(12, 2011):723-38].Prominent among the additional processes is the intense inflammationthat occurs in the vicinity of such synapses [WYSS-CORAY T, Rogers J.Inflammation in Alzheimer disease—a brief review of the basic scienceand clinical literature. Cold Spring Harb Perspect Med 2(1,2012):a006346, pp. 1-23; Jose Miguel RUBIO-PEREZ and Juana MariaMorillas-Ruiz. A Review: Inflammatory Process in Alzheimer's Disease,Role of Cytokines. The Scientific World Journal Volume 2012, Article ID756357, pp. 1-15]. Activated microglia and reactive astrocytes localizeto fibrillar plaques, and the phagocytic microglia engulf and degrade A

. However, chronically activated microglia release chemokines and acascade of damaging cytokines. Astrocytes also respond quickly withchanges in their morphology, antigenicity, and function, and, likemicroglia, these reactive states have initial beneficial but subsequentdestructive consequences. Overexpression of interleukin (IL)-1 is onesuch destructive consequence, which produces many reactions in a viciouscircle that cause dysfunction and neuronal death.

There is considerable evidence that the release of norepinephrine by thelocus ceruleus to the sites of the inflammation acts to reduce theinflammation. In so doing, the locus ceruleus protects itself fromdamage to the terminal fields of its axons, thereby limiting subsequentdeath of its own cells by what was described above as a Wallerian-likedegradation [COUNTS S E, Mufson E J. Noradrenaline activation ofneurotrophic pathways protects against neuronal amyloid toxicity. JNeurochem 113(3, 2010):649-60; WENK G L, McGann K, Hauss-Wegrzyniak B,Rosi S. The toxicity of tumor necrosis factor-alpha upon cholinergicneurons within the nucleus basalis and the role of norepinephrine in theregulation of inflammation: implications for Alzheimer's disease.Neuroscience 121(3, 2003):719-29; KALININ S, Gavrilyuk V, Polak P E,Vasser R, Zhao J, Heneka M T, Feinstein D L. Noradrenaline deficiency inbrain increases beta-amyloid plaque burden in an animal model ofAlzheimer's disease. Neurobiol Aging 28(8, 2007):1206-1214; HENEKA M T,Ramanathan M, Jacobs A H, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T,Sastre M, Galldiks N, Zimmer A, Hoehn M, Heiss W D, Klockgether T,Staufenbiel M. Locus ceruleus degeneration promotes Alzheimerpathogenesis in amyloid precursor protein 23 transgenic mice. JNeurosci. 26(5, 2006):1343-54; HENEKA M T, Nadrigny F, Regen T,Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-KurutzD, Walter J, Kirchhoff F, Hanisch U K, Kummer M P. Locus ceruleuscontrols Alzheimer's disease pathology by modulating microglialfunctions through norepinephrine. Proc Natl Acad Sci USA. 107(13,2010):6058-6063; JARDANHAZI-KURUTZ D, Kummer M P, Terwel D, Vogel K,Thiele A, Heneka M T. Distinct adrenergic system changes andneuroinflammation in response to induced locus ceruleus degeneration inAPP/PS1 transgenic mice. Neuroscience 176(2011):396-407; YANG J H, Lee EO, Kim S E, Suh Y H, Chong Y H. Norepinephrine differentially modulatesthe innate inflammatory response provoked by amyloid-ß peptide viaaction at ß-adrenoceptors and activation of cAMP/PKA pathway in humanTHP-1 macrophages. Exp Neurol 236(2, 2012):199-206; KONG Y, Ruan L, QianL, Liu X, Le Y. Norepinephrine promotes microglia to uptake and degradeamyloid beta peptide through upregulation of mouse formyl peptidereceptor 2 and induction of insulin-degrading enzyme. J Neurosci 30(35,2012):11848-11857; KALININ S, Polak P E, Lin S X, Sakharkar A J, PandeyS C, Feinstein D L. The noradrenaline precursor L-DOPS reduces pathologyin a mouse model of Alzheimer's disease. Neurobiol Aging 33(8,2012):1651-1663; HAMMERSCHMIDT T, Kummer M P, Terwel D, Martinez A,Gorji A, Pape H C, Rommelfanger K S, Schroeder J P, Stoll M, Schultze J,Weinshenker D, Heneka M T. Selective Loss of Noradrenaline ExacerbatesEarly Cognitive Dysfunction and Synaptic Deficits in APP/PS1 Mice. BiolPsychiatry. 2012 Aug. 9. Epub ahead of print, pp. 1-10; O'DONNELL J,Zeppenfeld D, McConnell E, Pena S, Nedergaard M. Norepinephrine: ANeuromodulator That Boosts the Function of Multiple Cell Types toOptimize CNS Performance. Neurochem Res. 2012 Jun. 21. (Epub ahead ofprint}, pp. 1-17].

Because stimulation of the vagus nerve can preferentially enhancenorepinephrine levels at selected central nervous sytem sites throughthe judicious choice of electrical stimulation parameters, its use ispotentially superior to the indiscriminant enhancement of norepinephrinelevels by pharmacological methods, because potential side effects wouldbe minimized by the former electrical stimulation method. Efficacy ofthe vagus nerve stimulation in this regard may be monitored andevaluated, for example, by imaging neuroinflammation in the brain[MASDEU J C, Kreisl W C, Berman K F. The neurobiology of Alzheimerdisease defined by neuroimaging. Curr Opin Neurol 25(4, 2012):410-420;JACOBS A H, Tavitian B; INMiND consortium. Noninvasive molecular imagingof neuroinflammation. J Cereb Blood Flow Metab 32(7, 2012):1393-1415;CHAUVEAU F, Boutin H, Van Camp N, Dolle F, Tavitian B. Nuclear imagingof neuroinflammation: a comprehensive review of [11C]PK11195challengers. Eur J Nucl Med Mol Imaging 35(12, 2008):2304-19].

Although the present invention is directed primarily to slowing orstopping the progression of the long-term course of AD, it is alsounderstood that the invention may have a shorter-term beneficial effecton the cognitive state of AD patients, particularly those who experiencecognitive fluctuations [ROBERTSON I H. A noradrenergic theory ofcognitive reserve: implications for Alzheimer's disease. NeurobiolAging. 2012 Jun. 26. (Epub ahead of print), pp. 1-11]. The role ofresting state networks in attentional fluctuations has heretofore beendiscussed almost entirely in terms of attention deficit hyperactivitydisorder (ADHD) and related disorders [SONUGA-BARKE E J, Castellanos FX. Spontaneous attentional fluctuations in impaired states andpathological conditions: a neurobiological hypothesis. Neurosci BiobehavRev. 2007; 31(7, 2007):977-86]. However, J U et al compared restingstate networks in subjects with mild or uncertain Alzheimer's diseasewith cognitive fluctuations, to those without cognitive fluctuations, aswell as to healthy controls, to assess whether cognitive fluctuationsare associated with abnormalities in resting state networks. Thesubjects with fluctuations had decreased daytime alertness and increasedfrequency of other sleep symptoms. The investigators found that therewas decreased connectivity in both default mode and dorsal attentionnetworks in the group with fluctuations (DMN and DAN, respectively inFIG. 1, with the self-referential network SRN being ordinarily beingconsidered part of DMN). Furthermore, there was decreasedanti-correlation between the two networks tested. Other resting statenetworks were not investigated, and correction for changes due to normalaging were not performed [Yo-El S. J U, Linda Larson-Prior, and JamesGalvin. Cognitive Fluctuations are Associated with Abnormalities inResting-State Functional Networks. SLEEP 2010 (the 24th Annual Meetingof the Associated Professional Sleep Societies, Jun. 6-9, 2010, SanAntonio, Tex.): Poster 70, Abstract 0109].

J U et al also proposed that individuals with cognitive fluctuationsconstitute a subset of individuals with mild cognitive impairment or AD,whose course of degeneration may be distinct from typical AD, so thatthe connections shown in FIG. 1 would not necessarily apply to cognitivefluctuators. According to FIG. 1, in a normal individual, SRN/DMN wouldactivate VAN which then activates DAN, and that activation woulddeactivate DMN, possibly with the aid of VAN, so that the individual canconcentrate on the task at hand without the distraction produced by anactive DMN. In the Alzheimer patient, the connections are altered, andthe networks themselves are altered. But according to FIG. 1, thealterations are likely to involve a decreased connectivity to VAN, suchthat VAN would not be able to perform its normal role in promotingconcentration on the part of the cognitive fluctuator. According to thepresent invention, stimulation of VAN by vagus nerve stimulation wouldcompensate for that altered VAN connectivity by providing extranorepinephrine to VAN, thereby resetting the networks of the patientfrom one temporarily trapped in an innatentive global state to one inwhich more normal concentration is possible.

Description of the Magnetic and Electrode-Based NerveStimulating/Modulating Devices

Methods and devices of the invention that are used to stimulate a vagusnerve will now be described. Either a magnetic stimulation device or anelectrode-based device may be used for that purpose. FIG. 2A is aschematic diagram of Applicant's magnetic nerve stimulating/modulatingdevice 301 for delivering impulses of energy to nerves for the treatmentof medical conditions such as dementia. As shown, device 301 may includean impulse generator 310; a power source 320 coupled to the impulsegenerator 310; a control unit 330 in communication with the impulsegenerator 310 and coupled to the power source 320; and a magneticstimulator coil 341 coupled via wires to impulse generator coil 310. Thestimulator coil 341 is toroidal in shape, due to its winding around atoroid of core material.

Although the magnetic stimulator coil 341 is shown in FIG. 2A to be asingle coil, in practice the coil may also comprise two or more distinctcoils, each of which is connected in series or in parallel to theimpulse generator 310. Thus, the coil 341 that is shown in FIG. 2Arepresents all the magnetic stimulator coils of the device collectively.In a preferred embodiment that is discussed below, coil 341 actuallycontains two coils that may be connected either in series or in parallelto the impulse generator 310.

The item labeled in FIG. 2A as 351 is a volume, surrounding the coil341, that is filled with electrically conducting medium. As shown, themedium not only encloses the magnetic stimulator coil, but is alsodeformable such that it is form-fitting when applied to the surface ofthe body. Thus, the sinuousness or curvature shown at the outer surfaceof the electrically conducting medium 351 corresponds also tosinuousness or curvature on the surface of the body, against which theconducting medium 351 is applied, so as to make the medium and bodysurface contiguous. As time-varying electrical current is passed throughthe coil 341, a magnetic field is produced, but because the coil windingis toroidal, the magnetic field is spatially restricted to the interiorof the toroid. An electric field and eddy currents are also produced.The electric field extends beyond the toroidal space and into thepatient's body, causing electrical currents and stimulation within thepatient. The volume 351 is electrically connected to the patient at atarget skin surface in order to significantly reduce the current passedthrough the coil 341 that is needed to accomplish stimulation of thepatient's nerve or tissue. In a preferred embodiment of the magneticstimulator that is discussed below, the conducting medium with which thecoil 341 is in contact need not completely surround the toroid.

The design of the magnetic stimulator 301, which is also adapted hereinfor use with surface electrodes, makes it possible to shape the electricfield that is used to selectively stimulate a relatively deep nerve suchas a vagus nerve in the patient's neck. Furthermore, the design producessignificantly less pain or discomfort (if any) to a patient thanstimulator devices that are currently known in the art. Conversely, fora given amount of pain or discomfort on the part of the patient (e.g.,the threshold at which such discomfort or pain begins), the designachieves a greater depth of penetration of the stimulus under the skin.

An alternate embodiment of the present invention is shown in FIG. 2B,which is a schematic diagram of an electrode-based nervestimulating/modulating device 302 for delivering impulses of energy tonerves for the treatment of medical conditions. As shown, device 302 mayinclude an impulse generator 310; a power source 320 coupled to theimpulse generator 310; a control unit 330 in communication with theimpulse generator 310 and coupled to the power source 320; andelectrodes 340 coupled via wires 345 to impulse generator 310. In apreferred embodiment, the same impulse generator 310, power source 320,and control unit 330 may be used for either the magnetic stimulator 301or the electrode-based stimulator 302, allowing the user to changeparameter settings depending on whether coils 341 or the electrodes 340are attached.

Although a pair of electrodes 340 is shown in FIG. 2B, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 340 that are shown in FIG. 2Brepresent all electrodes of the device collectively.

The item labeled in FIG. 2B as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Asdescribed below in connection with particular embodiments of theinvention, conducting medium in which the electrode 340 is embedded neednot completely surround an electrode. As also described below inconnection with a preferred embodiment, the volume 350 is electricallyconnected to the patient at a target skin surface in order to shape thecurrent density passed through an electrode 340 that is needed toaccomplish stimulation of the patient's nerve or tissue. The electricalconnection to the patient's skin surface is through an interface 351. Inone embodiment, the interface is made of an electrically insulating(dielectric) material, such as a thin sheet of Mylar. In that case,electrical coupling of the stimulator to the patient is capacitive. Inother embodiments, the interface comprises electrically conductingmaterial, such as the electrically conducting medium 350 itself, or anelectrically conducting or permeable membrane. In that case, electricalcoupling of the stimulator to the patient is ohmic. As shown, theinterface may be deformable such that it is form-fitting when applied tothe surface of the body. Thus, the sinuousness or curvature shown at theouter surface of the interface 351 corresponds also to sinuousness orcurvature on the surface of the body, against which the interface 351 isapplied, so as to make the interface and body surface contiguous.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's coils or electrodes. The signals areselected to be suitable for amelioration of a particular medicalcondition, when the signals are applied non-invasively to a target nerveor tissue via the coil 341 or electrodes 340. It is noted that nervestimulating/modulating device 301 or 302 may be referred to by itsfunction as a pulse generator. Patent application publicationsUS2005/0075701 and US2005/0075702, both to SHAFER, contain descriptionsof pulse generators that may be applicable to the present invention. Byway of example, a pulse generator is also commercially available, suchas Agilent 33522A Function/Arbitrary Waveform Generator, AgilentTechnologies, Inc., 5301 Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard, computer mouse, andtouchscreen, as well as any externally supplied physiological signals(see FIG. 8), analog-to-digital converters for digitizing externallysupplied analog signals (see FIG. 8), communication devices for thetransmission and receipt of data to and from external devices such asprinters and modems that comprise part of the system, hardware forgenerating the display of information on monitors that comprise part ofthe system, and busses to interconnect the above-mentioned components.Thus, the user may operate the system by typing instructions for thecontrol unit 330 at a device such as a keyboard and view the results ona device such as the system's computer monitor, or direct the results toa printer, modem, and/or storage disk. Control of the system may bebased upon feedback measured from externally supplied physiological orenvironmental signals. Alternatively, the control unit 330 may have acompact and simple structure, for example, wherein the user may operatethe system using only an on/off switch and power control wheel or knob.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes or coils, as well as the spatialdistribution of the electric field that is produced by the electrodes orcoils. The rise time and peak energy are governed by the electricalcharacteristics of the stimulator and electrodes or coils, as well as bythe anatomy of the region of current flow within the patient. In oneembodiment of the invention, pulse parameters are set in such as way asto account for the detailed anatomy surrounding the nerve that is beingstimulated [Bartosz SAWICKI, Robert Szmurło, Przemysław Płonecki, JacekStarzyński, Stanisław Wincenciak, Andrzej Rysz. Mathematical Modellingof Vagus Nerve Stimulation. pp. 92-97 in: Krawczyk, A. ElectromagneticField, Health and Environment: Proceedings of EHE'07. Amsterdam, 105Press, 2008]. Pulses may be monophasic, biphasic or polyphasic.Embodiments of the invention include those that are fixed frequency,where each pulse in a train has the same inter-stimulus interval, andthose that have modulated frequency, where the intervals between eachpulse in a train can be varied.

FIG. 2C illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively produced within the patient bythe stimulator coils or electrodes. As shown, a suitable electricalvoltage/current profile 400 for the blocking and/or modulating impulse410 to the portion or portions of a nerve may be achieved using pulsegenerator 310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the coil 341 or electrodes 340 that deliver the stimulating,blocking and/or modulating impulse 410 to the nerve. Nervestimulating/modulating device 301 or 302 may be externally poweredand/or recharged or may have its own power source 320. The parameters ofthe modulation signal 400, such as the frequency, amplitude, duty cycle,pulse width, pulse shape, etc., are preferably programmable. An externalcommunication device may modify the pulse generator programming toimprove treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes orcoils, the device disclosed in patent publication No. US2005/0216062 maybe employed. That patent publication discloses a multifunctionalelectrical stimulation (ES) system adapted to yield output signals foreffecting electromagnetic or other forms of electrical stimulation for abroad spectrum of different biological and biomedical applications,which produce an electric field pulse in order to non-invasivelystimulate nerves. The system includes an ES signal stage having aselector coupled to a plurality of different signal generators, eachproducing a signal having a distinct shape, such as a sine wave, asquare or a saw-tooth wave, or simple or complex pulse, the parametersof which are adjustable in regard to amplitude, duration, repetitionrate and other variables. Examples of the signals that may be generatedby such a system are described in a publication by LIBOFF [A. R. LIBOFF.Signal shapes in electromagnetic therapies: a primer. pp. 17-37 in:Bioelectromagnetic Medicine (Paul J. Rosch and Marko S. Markov, eds.).New York: Marcel Dekker (2004)]. The signal from the selected generatorin the ES stage is fed to at least one output stage where it isprocessed to produce a high or low voltage or current output of adesired polarity whereby the output stage is capable of yielding anelectrical stimulation signal appropriate for its intended application.Also included in the system is a measuring stage which measures anddisplays the electrical stimulation signal operating on the substancebeing treated, as well as the outputs of various sensors which senseprevailing conditions prevailing in this substance, whereby the user ofthe system can manually adjust the signal, or have it automaticallyadjusted by feedback, to provide an electrical stimulation signal ofwhatever type the user wishes, who can then observe the effect of thissignal on a substance being treated.

The stimulating, blocking and/or modulating impulse signal 410preferably has a frequency, an amplitude, a duty cycle, a pulse width, apulse shape, etc. selected to influence the therapeutic result, namely,stimulating, blocking and/or modulating some or all of the transmissionof the selected nerve. For example, the frequency may be about 1 Hz orgreater, such as between about 15 Hz to 100 Hz, more preferably around25 Hz. The modulation signal may have a pulse width selected toinfluence the therapeutic result, such as about 1 microseconds to about1000 microseconds. For example, the electric field induced or producedby the device within tissue in the vicinity of a nerve may be about 5 to600 V/m, preferably less than 100 V/m, and even more preferably lessthan 30 V/m. The gradient of the electric field may be greater than 2V/m/mm. More generally, the stimulation device produces an electricfield in the vicinity of the nerve that is sufficient to cause the nerveto depolarize and reach a threshold for action potential propagation,which is approximately 8 V/m at 1000 Hz. The modulation signal may havea peak voltage amplitude selected to influence the therapeutic result,such as about 0.2 volts or greater, such as about 0.2 volts to about 40volts.

An objective of the disclosed stimulators is to provide both nerve fiberselectivity and spatial selectivity. Spatial selectivity may be achievedin part through the design of the electrode or coil configuration, andnerve fiber selectivity may be achieved in part through the design ofthe stimulus waveform, but designs for the two types of selectivity areintertwined. This is because, for example, a waveform may selectivelystimulate only one of two nerves whether they lie close to one anotheror not, obviating the need to focus the stimulating signal onto only oneof the nerves [GRILL W and Mortimer J T. Stimulus waveforms forselective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375-385].These methods complement others that are used to achieve selective nervestimulation, such as the use of local anesthetic, application ofpressure, inducement of ischemia, cooling, use of ultrasound, gradedincreases in stimulus intensity, exploiting the absolute refractoryperiod of axons, and the application of stimulus blocks [John E. SWETTand Charles M. Bourassa. Electrical stimulation of peripheral nerve. In:Electrical Stimulation Research Techniques, Michael M. Patterson andRaymond P. Kesner, eds. Academic Press. (New York, 1981) pp. 243-295].

To date, the selection of stimulation waveform parameters for nervestimulation has been highly empirical, in which the parameters arevaried about some initially successful set of parameters, in an effortto find an improved set of parameters for each patient. A more efficientapproach to selecting stimulation parameters might be to select astimulation waveform that mimics electrical activity in the anatomicalregions that one is attempting stimulate indirectly, in an effort toentrain the naturally occurring electrical waveform, as suggested inU.S. Pat. No. 6,234,953, entitled Electrotherapy device using lowfrequency magnetic pulses, to THOMAS et al. and application numberUS20090299435, entitled Systems and methods for enhancing or affectingneural stimulation efficiency and/or efficacy, to GLINER et al. One mayalso vary stimulation parameters iteratively, in search of an optimalsetting [U.S. Pat. No. 7,869,885, entitled Threshold optimization fortissue stimulation therapy, to BEGNAUD et al]. However, some stimulationwaveforms, such as those described herein, are discovered by trial anderror, and then deliberately improved upon.

Invasive nerve stimulation typically uses square wave pulse signals.However, Applicant found that square waveforms are not ideal fornon-invasive stimulation as they produce excessive pain. Prepulses andsimilar waveform modifications have been suggested as methods to improveselectivity of nerve stimulation waveforms, but Applicant did not findthem ideal [Aleksandra VUCKOVIC, Marco Tosato and Johannes J Struijk. Acomparative study of three techniques for diameter selective fiberactivation in the vagal nerve: anodal block, depolarizing prepulses andslowly rising pulses. J. Neural Eng. 5 (2008): 275-286; AleksandraVUCKOVIC, Nico J. M. Rijkhoff, and Johannes J. Struijk. Different PulseShapes to Obtain Small Fiber Selective Activation by Anodal Blocking—ASimulation Study. IEEE Transactions on Biomedical Engineering 51(5,2004):698-706; Kristian HENNINGS. Selective Electrical Stimulation ofPeripheral Nerve Fibers: Accommodation Based Methods. Ph.D. Thesis,Center for Sensory-Motor Interaction, Aalborg University, Aalborg,Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive stimulation [M. I. JOHNSON,C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesic effects ofdifferent pulse patterns of transcutaneous electrical nerve stimulationon cold-induced pain in normal subjects. Journal of PsychosomaticResearch 35 (2/3, 1991):313-321; U.S. Pat. No. 7,734,340, entitledStimulation design for neuromodulation, to De Ridder]. However, burstsof sinusoidal pulses are a preferred stimulation waveform, as shown inFIGS. 2D and 2E. As seen there, individual sinusoidal pulses have aperiod of □, and a burst consists of N such pulses. This is followed bya period with no signal (the inter-burst period). The pattern of a burstfollowed by silent inter-burst period repeats itself with a period of T.For example, the sinusoidal period □ may be 200 microseconds; the numberof pulses per burst may be N=5; and the whole pattern of burst followedby silent inter-burst period may have a period of T=40000 microseconds,which is comparable to 25 Hz stimulation (a much smaller value of T isshown in FIG. 2E to make the bursts discernable). When these exemplaryvalues are used for T and τ, the waveform contains significant Fouriercomponents at higher frequencies (1/200 microseconds=5000/sec), ascompared with those contained in transcutaneous nerve stimulationwaveforms, as currently practiced.

Applicant is unaware of such a waveform having been used with vagusnerve stimulation, but a similar waveform has been used to stimulatemuscle as a means of increasing muscle strength in elite athletes.However, for the muscle strengthening application, the currents used(200 mA) may be very painful and two orders of magnitude larger thanwhat are disclosed herein. Furthermore, the signal used for musclestrengthening may be other than sinusoidal (e.g., triangular), and theparameters t, N, and T may also be dissimilar from the valuesexemplified above [A. DELITTO, M. Brown, M. J. Strube, S. J. Rose, andR. C. Lehman. Electrical stimulation of the quadriceps femoris in anelite weight lifter: a single subject experiment. Int J Sports Med10(1989):187-191; Alex R WARD, Nataliya Shkuratova. Russian ElectricalStimulation: The Early Experiments. Physical Therapy 82 (10, 2002):1019-1030; Yocheved LAUFER and Michal Elboim. Effect of Burst Frequencyand Duration of Kilohertz-Frequency Alternating Currents and ofLow-Frequency Pulsed Currents on Strength of Contraction, MuscleFatigue, and Perceived Discomfort. Physical Therapy 88 (10,2008):1167-1176; Alex R WARD. Electrical Stimulation UsingKilohertz-Frequency Alternating Current. Physical Therapy 89 (2,2009):181-190; J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J.Batt. The transfer of current through skin and muscle during electricalstimulation with sine, square, Russian and interferential waveforms.Journal of Medical Engineering and Technology 33 (2, 2009): 170-181;U.S. Pat. No. 4,177,819, entitled Muscle stimulating apparatus, toKOFSKY et al]. Burst stimulation has also been disclosed in connectionwith implantable pulse generators, but wherein the bursting ischaracteristic of the neuronal firing pattern itself [U.S. Pat. No.7,734,340 to DE RIDDER, entitled Stimulation design for neuromodulation;application US20110184486 to DE RIDDER, entitled Combination of tonicand burst stimulations to treat neurological disorders]. By way ofexample, the electric field shown in FIGS. 2D and 2E may have an E_(max)value of 17 V/m, which is sufficient to stimulate the nerve but issignificantly lower than the threshold needed to stimulate surroundingmuscle.

High frequency electrical stimulation is also known in the treatment ofback pain at the spine [Patent application US20120197369, entitledSelective high frequency spinal cord modulation for inhibiting pain withreduced side effects and associated systems and methods, to ALATARIS etal.; Adrian A L KAISY, Iris Smet, and Jean-Pierre Van Buyten. Analgeiaof axial low back pain with novel spinal neuromodulation. Posterpresentation #202 at the 2011 meeting of The American Academy of PainMedicine, held in National Harbor, Md., Mar. 24-27, 2011]. Those methodsinvolve high-frequency modulation in the range of from about 1.5 KHz toabout 50 KHz, which is applied to the patient's spinal cord region.However, such methods are different from the present invention because,for example, they is invasive; they do not involve a bursting waveform,as in the present invention; they necessarily involve A-delta and Cnerve fibers and the pain that those fibers produce, whereas the presentinvention does not; they may involve a conduction block applied at thedorsal root level, whereas the present invention may stimulate actionpotentials without blocking of such action potentials; and/or theyinvolve an increased ability of high frequency modulation to penetratethrough the cerebral spinal fluid, which is not relevant to the presentinvention. In fact, a likely explanation for the reduced back pain thatis produced by their use of frequencies from 10 to 50 KHz is that theapplied electrical stimulus at those frequencies causes permanent damageto the pain-causing nerves, whereas the present invention involves onlyreversible effects [LEE R C, Zhang D, Hannig J. Biophysical injurymechanisms in electrical shock trauma. Annu Rev Biomed Eng2(2000):477-509].

The use of feedback to generate the modulation signal 400 may result ina signal that is not periodic, particularly if the feedback is producedfrom sensors that measure naturally occurring, time-varying aperiodicphysiological signals from the patient (see FIG. 8). In fact, theabsence of significant fluctuation in naturally occurring physiologicalsignals from a patient is ordinarily considered to be an indication thatthe patient is in ill health. This is because a pathological controlsystem that regulates the patient's physiological variables may havebecome trapped around only one of two or more possible steady states andis therefore unable to respond normally to external and internalstresses. Accordingly, even if feedback is not used to generate themodulation signal 400, it may be useful to artificially modulate thesignal in an aperiodic fashion, in such a way as to simulatefluctuations that would occur naturally in a healthy individual. Thus,the noisy modulation of the stimulation signal may cause a pathologicalphysiological control system to be reset or undergo a non-linear phasetransition, through a mechanism known as stochastic resonance [B. SUKI,A. Alencar, M. K. Sujeer, K. R. Lutchen, J. J. Collins, J. S. Andrade,E. P. Ingenito, S. Zapperi, H. E. Stanley, Life-support system benefitsfrom noise, Nature 393 (1998) 127-128; W Alan C MUTCH, M Ruth Graham,Linda G Girling and John F Brewster. Fractal ventilation enhancesrespiratory sinus arrhythmia. Respiratory Research 2005, 6:41, pp. 1-9].

So, in one embodiment of the present invention, the modulation signal400, with or without feedback, will stimulate the selected nerve fibersin such a way that one or more of the stimulation parameters (power,frequency, and others mentioned herein) are varied by sampling astatistical distribution having a mean corresponding to a selected, orto a most recent running-averaged value of the parameter, and thensetting the value of the parameter to the randomly sampled value. Thesampled statistical distributions will comprise Gaussian and 1/f,obtained from recorded naturally occurring random time series or bycalculated formula. Parameter values will be so changed periodically, orat time intervals that are themselves selected randomly by samplinganother statistical distribution, having a selected mean and coefficientof variation, where the sampled distributions comprise Gaussian andexponential, obtained from recorded naturally occurring random timeseries or by calculated formula.

In another embodiment, devices in accordance with the present inventionare provided in a “pacemaker” type form, in which electrical impulses410 are generated to a selected region of the nerve by a stimulatordevice on an intermittent basis, to create in the patient a lowerreactivity of the nerve.

Preferred Embodiments of the Magnetic Stimulator

A preferred embodiment of magnetic stimulator coil 341 comprises atoroidal winding around a core consisting of high-permeability material(e.g., Supermendur), embedded in an electrically conducting medium.Toroidal coils with high permeability cores have been theoreticallyshown to greatly reduce the currents required for transcranial (TMS) andother forms of magnetic stimulation, but only if the toroids areembedded in a conducting medium and placed against tissue with no airinterface [Rafael CARBUNARU and Dominique M. Durand. Toroidal coilmodels for transcutaneous magnetic stimulation of nerves. IEEETransactions on Biomedical Engineering 48 (4, 2001): 434-441; RafaelCarbunaru FAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph.D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999, (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.)].

Although Carbunaru and Durand demonstrated that it is possible toelectrically stimulate a patient transcutaneously with such a device,they made no attempt to develop the device in such a way as to generallyshape the electric field that is to stimulate the nerve. In particular,the electric fields that may be produced by their device are limited tothose that are radially symmetric at any given depth of stimulation intothe patient (i.e, z and p are used to specify location of the field, notx, y, and z). This is a significant limitation, and it results in adeficiency that was noted in FIG. 6 of their publication: “at largedepths of stimulation, the threshold current [in the device's coil] forlong axons is larger than the saturation current of the coil.Stimulation of those axons is only possible at low threshold points suchas bending sites or tissue conductivity inhomogeneities”. Thus, fortheir device, varying the parameters that they considered, in order toincrease the electric field or its gradient in the vicinity of a nerve,may come at the expense of limiting the field's physiologicaleffectiveness, such that the spatial extent of the field of stimulationmay be insufficient to modulate the target nerve's function. Yet, suchlong axons are precisely what we may wish to stimulate in therapeuticinterventions, such as the ones disclosed herein.

Accordingly, it is an objective of the present invention to shape anelongated electric field of effect that can be oriented parallel to sucha long nerve. The term “shape an electric field” as used herein means tocreate an electric field or its gradient that is generally not radiallysymmetric at a given depth of stimulation in the patient, especially afield that is characterized as being elongated or finger-like, andespecially also a field in which the magnitude of the field in somedirection may exhibit more than one spatial maximum (i.e. may be bimodalor multimodal) such that the tissue between the maxima may contain anarea across which induced current flow is restricted. Shaping of theelectric field refers both to the circumscribing of regions within whichthere is a significant electric field and to configuring the directionsof the electric field within those regions. The shaping of the electricfield is described in terms of the corresponding field equations incommonly assigned application US20110125203 (application Ser. No.12/964,050), entitled Magnetic stimulation devices and methods oftherapy, to SIMON et al., which is hereby incorporated by reference.

Thus, the present invention differs from the device disclosed byCARBUNARU and Durand by deliberately shaping an electric field that isused to transcutaneously stimulate the patient. Whereas the toroid inthe CARBUNARU and Durand publication was immersed in a homogeneousconducting half-space, this is not necessarily the case for ourinvention. Although our invention will generally have some continuouslyconducting path between the device's coil and the patient's skin, theconducting medium need not totally immerse the coil, and there may beinsulating voids within the conducting medium. For example, if thedevice contains two toroids, conducting material may connect each of thetoroids individually to the patient's skin, but there may be aninsulating gap (from air or some other insulator) between the surfacesat which conducting material connected to the individual toroids contactthe patient. Furthermore, the area of the conducting material thatcontacts the skin may be made variable, by using an aperture adjustingmechanism such as an iris diaphragm. As another example, if the coil iswound around core material that is laminated, with the core in contactwith the device's electrically conducting material, then the laminationmay be extended into the conducting material in such a way as to directthe induced electrical current between the laminations and towards thesurface of the patient's skin. As another example, the conductingmaterial may pass through apertures in an insulated mesh beforecontacting the patient's skin, creating thereby an array of electricfield maxima.

In the dissertation cited above, Carbunaru—FAIERSTEIN made no attempt touse conducting material other than agar in a KCl solution, and he madeno attempt to devise a device that could be conveniently and safelyapplied to a patient's skin, at an arbitrary angle without theconducting material spilling out of its container. It is therefore anobjective of the present invention to disclose conducting material thatcan be used not only to adapt the conductivity of the conductingmaterial and select boundary conditions, thereby shaping the electricfields and currents as described above, but also to create devices thatcan be applied practically to any surface of the body. The volume of thecontainer containing electrically conducting medium is labeled in FIG.2A as 351. Use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 to 0.1of the current conventionally applied to a magnetic stimulation coil.This allows for minimal heating of the coil(s) and deeper tissuestimulation. However, application of the conducting medium to thesurface of the patient is difficult to perform in practice because thetissue contours (head, arms, legs, neck, etc.) are not planar. To solvethis problem, in the preferred embodiment of the present invention, thetoroidal coil is embedded in a structure which is filled with aconducting medium having approximately the same conductivity as muscletissue, as now described.

In one embodiment of the invention, the container contains holes so thatthe conducting material (e.g., a conducting gel) can make physicalcontact with the patient's skin through the holes. For example, theconducting medium 351 may comprise a chamber surrounding the coil,filled with a conductive gel that has the approximate viscosity andmechanical consistency of gel deodorant (e.g., Right Guard Clear Gelfrom Dial Corporation, 15501 N. Dial Boulevard, Scottsdale Ariz. 85260,one composition of which comprises aluminum chlorohydrate, sorbitol,propylene glycol, polydimethylsiloxanes Silicon oil, cyclomethicone,ethanol/SD Alcohol 40, dimethicone copolyol, aluminum zirconiumtetrachlorohydrex gly, and water). The gel, which is less viscous thanconventional electrode gel, is maintained in the chamber with a mesh ofopenings at the end where the device is to contact the patient's skin.The gel does not leak out, and it can be dispensed with a simple screwdriven piston.

In another embodiment, the container itself is made of a conductingelastomer (e.g., dry carbon-filled silicone elastomer), and electricalcontact with the patient is through the elastomer itself, possiblythrough an additional outside coating of conducting material. In someembodiments of the invention, the conducting medium may be a balloonfilled with a conducting gel or conducting powders, or the balloon maybe constructed extensively from deformable conducting elastomers. Theballoon conforms to the skin surface, removing any air, thus allowingfor high impedance matching and conduction of large electric fields into the tissue. A device such as that disclosed in U.S. Pat. No.7,591,776, entitled Magnetic stimulators and stimulating coils, toPHILLIPS et al. may conform the coil itself to the contours of the body,but in the preferred embodiment, such a curved coil is also enclosed bya container that is filled with a conducting medium that deforms to becontiguous with the skin.

Agar can also be used as part of the conducting medium, but it is notpreferred, because agar degrades in time, is not ideal to use againstskin, and presents difficulties with cleaning the patient and stimulatorcoil. Use of agar in a 4M KCl solution as a conducting medium wasmentioned in the above-cited dissertation: Rafael Carbunaru FAIERSTEIN,Coil Designs for Localized and Efficient Magnetic Stimulation of theNervous System. Ph.D. Dissertation, Department of BiomedicalEngineering, Case Western Reserve, May, 1999, page 117 (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.). However, thatpublication makes no mention or suggestion of placing the agar in aconducting elastomeric balloon, or other deformable container so as toallow the conducting medium to conform to the generally non-planarcontours of a patient's skin having an arbitrary orientation. In fact,that publication describes the coil as being submerged in a containerfilled with an electrically conducting solution. If the coil andcontainer were placed on a body surface that was oriented in thevertical direction, then the conducting solution would spill out, makingit impossible to stimulate the body surface in that orientation. Incontrast, the present invention is able to stimulate body surfaceshaving arbitrary orientation.

That dissertation also makes no mention of a dispensing method wherebythe agar would be made contiguous with the patient's skin. A layer ofelectrolytic gel is said to have been applied between the skin and coil,but the configuration was not described clearly in the publication. Inparticular, no mention is made of the electrolytic gel being in contactwith the agar.

Rather than using agar as the conducting medium, the coil can instead beembedded in a conducting solution such as 1-10% NaCl, contacting anelectrically conducting interface to the human tissue. Such an interfaceis used as it allows current to flow from the coil into the tissue andsupports the medium-surrounded toroid so that it can be completelysealed. Thus, the interface is material, interposed between theconducting medium and patient's skin, that allows the conducting medium(e.g., saline solution) to slowly leak through it, allowing current toflow to the skin. Several interfaces are disclosed as follows.

One interface comprises conducting material that is hydrophilic, such asTecophlic from The Lubrizol Corporation, 29400 Lakeland Boulevard,Wickliffe, Ohio 44092. It absorbs from 10-100% of its weight in water,making it highly electrically conductive, while allowing only minimalbulk fluid flow.

Another material that may be used as an interface is a hydrogel, such asthat used on standard EEG, EKG and TENS electrodes [Rylie A GREEN,Sungchul Baek, Laura A Poole-Warren and Penny J Martens. Conductingpolymer-hydrogels for medical electrode applications. Sci. Technol. Adv.Mater. 11 (2010) 014107 (13pp)]. For example it may be the followinghypoallergenic, bacteriostatic electrode gel: SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.

A third type of interface may be made from a very thin material with ahigh dielectric constant, such as those used to make capacitors. Forexample, Mylar can be made in submicron thicknesses and has a dielectricconstant of about 3. Thus, at stimulation frequencies of severalkilohertz or greater, the Mylar will capacitively couple the signalthrough it because it will have an impedance comparable to that of theskin itself. Thus, it will isolate the toroid and the solution it isembedded in from the tissue, yet allow current to pass.

The preferred embodiment of the magnetic stimulator coil 341 in FIG. 2Areduces the volume of conducting material that must surround a toroidalcoil, by using two toroids, side-by-side, and passing electrical currentthrough the two toroidal coils in opposite directions. In thisconfiguration, the induced current will flow from the lumen of onetoroid, through the tissue and back through the lumen of the other,completing the circuit within the toroids' conducting medium. Thus,minimal space for the conducting medium is required around the outsideof the toroids at positions near from the gap between the pair of coils.An additional advantage of using two toroids in this configuration isthat this design will greatly increase the magnitude of the electricfield gradient between them, which is crucial for exciting long,straight axons such as the vagus nerve and certain other peripheralnerves.

This preferred embodiment of the magnetic stimulation device is shown inFIG. 3. FIGS. 3A and 3B respectively provide top and bottom views of theouter surface of the toroidal magnetic stimulator 30. FIGS. 3C and 3Drespectively provide top and bottom views of the toroidal magneticstimulator 30, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 3A-3D all show a mesh 31 with openings that permit a conductinggel to pass from the inside of the stimulator to the surface of thepatient's skin at the location of nerve or tissue stimulation. Thus, themesh with openings 31 is the part of the stimulator that is applied tothe skin of the patient.

FIGS. 3B-3D show openings at the opposite end of the stimulator 30. Oneof the openings is an electronics port 32 through which wires pass fromthe stimulator coil(s) to the impulse generator (310 in FIG. 2A). Thesecond opening is a conducting gel port 33 through which conducting gelmay be introduced into the stimulator 30 and through which ascrew-driven piston arm may be introduced to dispense conducting gelthrough the mesh 31. The gel itself will be contained withincylindrical-shaped but interconnected conducting medium chambers 34 thatare shown in FIGS. 3C and 3D. The depth of the conducting mediumchambers 34, which is approximately the height of the long axis of thestimulator, affects the magnitude of the electric fields and currentsthat are induced by the device [Rafael CARBUNARU and Dominique M.Durand. Toroidal coil models for transcutaneous magnetic stimulation ofnerves. IEEE Transactions on Biomedical Engineering. 48 (4, 2001):434-441].

FIGS. 3C and 3D also show the coils of wire 35 that are wound aroundtoroidal cores 36, consisting of high-permeability material (e.g.,Supermendur). Lead wires (not shown) for the coils 35 pass from thestimulator coil(s) to the impulse generator (310 in FIG. 1) via theelectronics port 32. Different circuit configurations are contemplated.If separate lead wires for each of the coils 35 connect to the impulsegenerator (i.e., parallel connection), and if the pair of coils arewound with the same handedness around the cores, then the design is forcurrent to pass in opposite directions through the two coils. On theother hand, if the coils are wound with opposite handedness around thecores, then the lead wires for the coils may be connected in series tothe impulse generator, or if they are connected to the impulse generatorin parallel, then the design is for current to pass in the samedirection through both coils.

As seen in FIGS. 3C and 3D, the coils 35 and cores 36 around which theyare wound are mounted as close as practical to the corresponding mesh 31with openings through which conducting gel passes to the surface of thepatient's skin. As seen in FIG. 3D, each coil and the core around whichit is wound is mounted in its own housing 37, the function of which isto provide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium.

Different diameter toroidal coils and windings may be preferred fordifferent applications. For a generic application, the outer diameter ofthe core may be typically 1 to 5 cm, with an inner diameter typically0.5 to 0.75 of the outer diameter. The coil's winding around the coremay be typically 3 to 250 in number, depending on the core diameter anddepending on the desired coil inductance.

Signal generators for magnetic stimulators have been described forcommercial systems [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006], as well as for customdesigns for a control unit 330, impulse generator 310 and power source320 [Eric BASHAM, Zhi Yang, Natalia Tchemodanov, and Wentai Liu.Magnetic Stimulation of Neural Tissue: Techniques and System Design. pp293-352, In: Implantable Neural Prostheses 1, Devices and Applications,D. Zhou and E. Greenbaum, eds., New York: Springer (2009); U.S. Pat. No.7,744,523, entitled Drive circuit for magnetic stimulation, to CharlesM. Epstein; U.S. Pat. No. 5,718,662, entitled Apparatus for the magneticstimulation of cells or tissue, to Reza Jalinous; U.S. Pat. No.5,766,124, entitled Magnetic stimulator for neuro-muscular tissue, toPoison]. Conventional magnetic nerve stimulators use a high currentimpulse generator that may produce discharge currents of 5,000 amps ormore, which is passed through the stimulator coil, and which therebyproduces a magnetic pulse. Typically, a transformer charges a capacitorin the impulse generator 310, which also contains circuit elements thatlimit the effect of undesirable electrical transients. Charging of thecapacitor is under the control of a control unit 330, which acceptsinformation such as the capacitor voltage, power and other parametersset by the user, as well as from various safety interlocks within theequipment that ensure proper operation, and the capacitor is thendischarged through the coil via an electronic switch (e.g., a controlledrectifier) when the user wishes to apply the stimulus.

Greater flexibility is obtained by adding to the impulse generator abank of capacitors that can be discharged at different times. Thus,higher impulse rates may be achieved by discharging capacitors in thebank sequentially, such that recharging of capacitors is performed whileother capacitors in the bank are being discharged. Furthermore, bydischarging some capacitors while the discharge of other capacitors isin progress, by discharging the capacitors through resistors havingvariable resistance, and by controlling the polarity of the discharge,the control unit may synthesize pulse shapes that approximate anarbitrary function.

The design and methods of use of impulse generators, control units, andstimulator coils for magnetic stimulators are informed by the designsand methods of use of impulse generators, control units, and electrodes(with leads) for comparable completely electrical nerve stimulators, butdesign and methods of use of the magnetic stimulators must take intoaccount many special considerations, making it generally notstraightforward to transfer knowledge of completely electricalstimulation methods to magnetic stimulation methods. Such considerationsinclude determining the anatomical location of the stimulation anddetermining the appropriate pulse configuration [OLNEY R K, So Y T,Goodin D S, Aminoff M J. A comparison of magnetic and electricstimulation of peripheral nerves. Muscle Nerve 1990:13:957-963; J.NILSSON, M. Panizza, B. J. Roth et al. Determining the site ofstimulation during magnetic stimulation of the peripheral nerve,Electroencephalographs and clinical neurophysiology 85(1992): 253-264;Nafia A L-MUTAWALY, Hubert de Bruin, and Gary Hasey. The effects ofpulse configuration on magnetic stimulation. Journal of ClinicalNeurophysiology 20(5):361-370, 2003].

Furthermore, a potential practical disadvantage of using magneticstimulator coils is that they may overheat when used over an extendedperiod of time. Use of the above-mentioned toroidal coil and containerof electrically conducting medium addresses this potential disadvantage.However, because of the poor coupling between the stimulating coils andthe nerve tissue, large currents are nevertheless required to reachthreshold electric fields. At high repetition rates, these currents canheat the coils to unacceptable levels in seconds to minutes depending onthe power levels and pulse durations and rates. Two approaches toovercome heating are to cool the coils with flowing water or air or toincrease the magnetic fields using ferrite cores (thus allowing smallercurrents). For some applications where relatively long treatment timesat high stimulation frequencies may be required, neither of these twoapproaches are adequate. Water-cooled coils overheat in a few minutes.Ferrite core coils heat more slowly due to the lower currents and heatcapacity of the ferrite core, but also cool off more slowly and do notallow for water-cooling since the ferrite core takes up the volume wherethe cooling water would flow.

A solution to this problem is to use a fluid which containsferromagnetic particles in suspension like a ferrofluid, ormagnetorheological fluid as the cooling material. Ferrofluids arecolloidal mixtures composed of nanoscale ferromagnetic, orferrimagnetic, particles suspended in a carrier fluid, usually anorganic solvent or water. The ferromagnetic nanoparticles are coatedwith a surfactant to prevent their agglomeration (due to van der Waalsforces and magnetic forces). Ferrofluids have a higher heat capacitythan water and will thus act as better coolants. In addition, the fluidwill act as a ferrite core to increase the magnetic field strength.Also, since ferrofluids are paramagnetic, they obey Curie's law, andthus become less magnetic at higher temperatures. The strong magneticfield created by the magnetic stimulator coil will attract coldferrofluid more than hot ferrofluid thus forcing the heated ferrofluidaway from the coil. Thus, cooling may not require pumping of theferrofluid through the coil, but only a simple convective system forcooling. This is an efficient cooling method which may require noadditional energy input [U.S. Pat. No. 7,396,326 and publishedapplications US2008/0114199, US2008/0177128, and US2008/0224808, allentitled Ferrofluid cooling and acoustical noise reduction in magneticstimulators, respectively to Ghiron et al., Riehl et al., Riehl et al.and Ghiron et al.].

Magnetorheological fluids are similar to ferrofluids but contain largermagnetic particles which have multiple magnetic domains rather than thesingle domains of ferrofluids. [U.S. Pat. No. 6,743,371, Magnetosensitive fluid composition and a process for preparation thereof, toJohn et al.]. They can have a significantly higher magnetic permeabilitythan ferrofluids and a higher volume fraction of iron to carrier.Combinations of magnetorheological and ferrofluids may also be used [M TLOPEZ-LOPEZ, P Kuzhir, S Lacis, G Bossis, F Gonzalez-Caballero and J D GDuran. Magnetorheology for suspensions of solid particles dispersed inferrofluids. J. Phys.: Condens. Matter 18 (2006) S2803-S2813; LadislauVEKAS. Ferrofluids and Magnetorheological Fluids. Advances in Scienceand Technology Vol. 54 (2008) pp 127-136.].

Commercially available magnetic stimulators include circular, parabolic,figure-of-eight (butterfly), and custom designs that are availablecommercially [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006]. Additional embodimentsof the magnetic stimulator coil 341 have been described [No. U.S. Pat.No. 6,179,770, entitled Coil assemblies for magnetic stimulators, toStephen Mould; Kent DAVEY. Magnetic Stimulation Coil and Circuit Design.IEEE Transactions on Biomedical Engineering, Vol. 47 (No. 11, November2000): 1493-1499]. Many of the problems that are associated with suchconventional magnetic stimulators, e.g., the complexity of theimpulse-generator circuitry and the problem with overheating, arelargely avoided by the toroidal design shown in FIG. 3.

Thus, use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 to 0.1of the current conventionally applied to a magnetic stimulation coil.Therefore, with the present invention, it is possible to generatewaveforms shown in FIG. 2 with relatively simple, low-power circuitsthat are powered by batteries. The circuits may be enclosed within a box38 as shown in FIG. 3E, or the circuits may be attached to thestimulator itself (FIG. 3A-3D) to be used as a hand-held device. Ineither case, control over the unit may be made using only an on/offswitch and power knob. The only other component that may be needed mightbe a cover 39 to keep the conducting fluid from leaking or drying outbetween uses. The currents passing through the coils of the magneticstimulator will saturate its core (e.g., 0.1 to 2 Tesla magnetic fieldstrength for Supermendur core material). This will require approximately0.5 to 20 amperes of current being passed through each coil, typically 2amperes, with voltages across each coil of 10 to 100 volts. The currentis passed through the coils in bursts of pulses, as described inconnection with FIGS. 2D and 2E, shaping an elongated electrical fieldof effect.

Preferred Embodiments of the Electrode-Based Stimulator

In another embodiment of the invention, electrodes applied to thesurface of the neck, or to some other surface of the body, are used tonon-invasively deliver electrical energy to a nerve, instead ofdelivering the energy to the nerve via a magnetic coil. The vagus nervehas been stimulated previously non-invasively using electrodes appliedvia leads to the surface of the skin. U.S. Pat. No. 7,340,299, entitledMethods of indirectly stimulating the vagus nerve to achieve controlledasystole, to John D. PUSKAS, discloses the stimulation of the vagusnerve using electrodes placed on the neck of the patient, but thatpatent is unrelated to the treatment of dementia. Non-invasiveelectrical stimulation of the vagus nerve has also been described inJapanese patent application JP2009233024A with a filing date of Mar. 26,2008, entitled Vagus Nerve Stimulation System, to Fukui YOSHIHOTO, inwhich a body surface electrode is applied to the neck to stimulate thevagus nerve electrically. However, that application pertains to thecontrol of heart rate and is unrelated to the treatment of dementia.

Patent application US2010/0057154, entitled Device and method for thetransdermal stimulation of a nerve of the human body, to DIETRICH etal., discloses a non-invasive transcutaneous/transdermal method forstimulating the vagus nerve, at an anatomical location where the vagusnerve has paths in the skin of the external auditory canal. Theirnon-invasive method involves performing electrical stimulation at thatlocation, using surface stimulators that are similar to those used forperipheral nerve and muscle stimulation for treatment of pain(transdermal electrical nerve stimulation), muscle training (electricalmuscle stimulation) and electroacupuncture of defined meridian points.The method used in that application is similar to the ones used in U.S.Pat. No. 4,319,584, entitled Electrical pulse acupressure system, toMcCALL, for electroacupuncture; U.S. Pat. No. 5,514,175 entitledAuricular electrical stimulator, to KIM et al., for the treatment ofpain; and U.S. Pat. No. 4,966,164, entitled Combined sound generatingdevice and electrical acupuncture device and method for using the same,to COLSEN et al., for combined sound/electroacupuncture. A relatedapplication is US2006/0122675, entitled Stimulator for auricular branchof vagus nerve, to LIBBUS et al. Similarly, U.S. Pat. No. 7,386,347,entitled Electric stimilator for alpha-wave derivation, to CHUNG et al.,described electrical stimulation of the vagus nerve at the ear. Patentapplication US2008/0288016, entitled Systems and Methods for StimulatingNeural Targets, to AMURTHUR et al., also discloses electricalstimulation of the vagus nerve at the ear. However, none of thedisclosures in these patents or patent applications for electricalstimulation of the vagus nerve at the ear are used to treat dementia.

Embodiments of the present invention may differ with regard to thenumber of electrodes that are used, the distance between electrodes, andwhether disk or ring electrodes are used. In preferred embodiments ofthe method, one selects the electrode configuration for individualpatients, in such a way as to optimally focus electric fields andcurrents onto the selected nerve, without generating excessive currentson the surface of the skin. This tradeoff between focality and surfacecurrents is described by DATTA et al. [Abhishek DATTA, Maged Elwassif,Fortunato Battaglia and Marom Bikson. Transcranial current stimulationfocality using disc and ring electrode configurations: FEM analysis. J.Neural Eng. 5 (2008): 163-174]. Although DATTA et al. are addressing theselection of electrode configuration specifically for transcranialcurrent stimulation, the principles that they describe are applicable toperipheral nerves as well [RATTAY F. Analysis of models forextracellular fiber stimulation. IEEE Trans. Biomed. Eng. 36 (1989):676-682].

Considering that the nerve stimulating device 301 in FIG. 2A and thenerve stimulating device 302 in FIG. 2B both control the shape ofelectrical impulses, their functions are analogous, except that onestimulates nerves via a pulse of a magnetic field, and the otherstimulates nerves via an electrical pulse applied through surfaceelectrodes. Accordingly, general features recited for the nervestimulating device 301 apply as well to the latter stimulating device302 and will not be repeated here. The preferred parameters for eachnerve stimulating device are those that produce the desired therapeuticeffects.

A preferred embodiment of an electrode-based stimulator is shown in FIG.4A. A cross-sectional view of the stimulator along its long axis isshown in FIG. 4B. As shown, the stimulator (730) comprises two heads(731) and a body (732) that joins them. Each head (731) contains astimulating electrode. The body of the stimulator (732) contains theelectronic components and battery (not shown) that are used to generatethe signals that drive the electrodes, which are located behind theinsulating board (733) that is shown in FIG. 4B. However, in otherembodiments of the invention, the electronic components that generatethe signals that are applied to the electrodes may be separate, butconnected to the electrode head (731) using wires. Furthermore, otherembodiments of the invention may contain a single such head or more thantwo heads.

Heads of the stimulator (731) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes (not shown), or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation power may beadjusted with a wheel (734) that also serves as an on/off switch. Alight (735) is illuminated when power is being supplied to thestimulator. An optional cap may be provided to cover each of thestimulator heads (731), to protect the device when not in use, to avoidaccidental stimulation, and to prevent material within the head fromleaking or drying. Thus, in this embodiment of the invention, mechanicaland electronic components of the stimulator (impulse generator, controlunit, and power source) are compact, portable, and simple to operate.

Details of one embodiment of the stimulator head are shown in FIGS. 4Cand 4D. The electrode head may be assembled from a disc withoutfenestration (743), or alternatively from a snap-on cap that serves as atambour for a dielectric or conducting membrane, or alternatively thehead may have a solid fenestrated head-cup. The electrode may also be ascrew (745). The preferred embodiment of the disc (743) is a solid,ordinarily uniformly conducting disc (e.g., metal such as stainlesssteel), which is possibly flexible in some embodiments. An alternateembodiment of the disc is a non-conducting (e.g., plastic) aperturescreen that permits electrical current to pass through its apertures,e.g., through an array of apertures (fenestration). The electrode (745,also 340 in FIG. 2B) seen in each stimulator head may have the shape ofa screw that is flattened on its tip. Pointing of the tip would make theelectrode more of a point source, such that the equations for theelectrical potential may have a solution corresponding more closely to afar-field approximation. Rounding of the electrode surface or making thesurface with another shape will likewise affect the boundary conditionsthat determine the electric field. Completed assembly of the stimulatorhead is shown in FIG. 4D, which also shows how the head is attached tothe body of the stimulator (747).

If a membrane is used, it ordinarily serves as the interface shown as351 in FIG. 2B. For example, the membrane may be made of a dielectric(non-conducting) material, such as a thin sheet of Mylar(biaxially-oriented polyethylene terephthalate, also known as BoPET). Inother embodiments, it may be made of conducting material, such as asheet of Tecophlic material from Lubrizol Corporation, 29400 LakelandBoulevard, Wickliffe, Ohio 44092. In one embodiment, apertures of thedisc may be open, or they may be plugged with conducting material, forexample, KM10T hydrogel from Katecho Inc., 4020 Gannett Ave., Des MoinesIowa 50321. If the apertures are so-plugged, and the membrane is made ofconducting material, the membrane becomes optional, and the plug servesas the interface 351 shown in FIG. 2B.

The head-cup (744) is filled with conducting material (350 in FIG. 2B),for example, SIGNAGEL Electrode Gel from Parker Laboratories, Inc., 286Eldridge Rd., Fairfield N.J. 07004. The head-cup (744) and body of thestimulator are made of a non-conducting material, such as acrylonitrilebutadiene styrene. The depth of the head-cup from its top surface to theelectrode may be between one and six centimeters. The head-cup may havea different curvature than what is shown in FIG. 4, or it may be tubularor conical or have some other inner surface geomety that will affect theNeumann boundary conditions that determine the electric field strength.

If an outer membrane is used and is made of conducting materials, andthe disc (743) in FIG. 4C is made of solid conducting materials such asstainless steel, then the membrane becomes optional, in which case thedisc may serve as the interface 351 shown in FIG. 2B. Thus, anembodiment without the membrane is shown in FIGS. 4C and 4D. Thisversion of the device comprises a solid (but possibly flexible in someembodiments) conducting disc that cannot absorb fluid, thenon-conducting stimulator head (744) into or onto which the disc isplaced, and the electrode (745), which is also a screw. It is understoodthat the disc (743) may have an anisotropic material or electricalstructure, for example, wherein a disc of stainless steel has a grain,such that the grain of the disc should be rotated about its location onthe stimulator head, in order to achieve optimal electrical stimulationof the patient. As seen in FIG. 4D, these items are assembled to becomea sealed stimulator head that is attached to the body of the stimulator(747). The disc (743) may screw into the stimulator head (744), it maybe attached to the head with adhesive, or it may be attached by othermethods that are known in the art. The chamber of the stimulatorhead-cup is filled with a conducting gel, fluid, or paste, and becausethe disc (743) and electrode (745) are tightly sealed against thestimulator head-cup (744), the conducting material within the stimulatorhead cannot leak out. In addition, this feature allows the user toeasily clean the outer surface of the device (e.g., with isopropylalcohol or similar disinfectant), avoiding potential contaminationduring subsequent uses of the device.

In some embodiments, the interface comprises a fluid permeable materialthat allows for passage of current through the permeable portions of thematerial. In these embodiments, a conductive medium (such as a gel) ispreferably situated between the electrode(s) and the permeableinterface. The conductive medium provides a conductive pathway forelectrons to pass through the permeable interface to the outer surfaceof the interface and to the patient's skin.

In other embodiments of the present invention, the interface (351 inFIG. 2B) is made from a very thin material with a high dielectricconstant, such as material used to make capacitors. For example, it maybe Mylar having a submicron thickness (preferably in the range 0.5 to1.5 microns) having a dielectric constant of about 3. Because one sideof Mylar is slick, and the other side is microscopically rough, thepresent invention contemplates two different configurations: one inwhich the slick side is oriented towards the patient's skin, and theother in which the rough side is so-oriented. Thus, at stimulationFourier frequencies of several kilohertz or greater, the dielectricinterface will capacitively couple the signal through itself, because itwill have an impedance comparable to that of the skin. Thus, thedielectric interface will isolate the stimulator's electrode from thetissue, yet allow current to pass. In one embodiment of the presentinvention, non-invasive electrical stimulation of a nerve isaccomplished essentially substantially capacitively, which reduces theamount of ohmic stimulation, thereby reducing the sensation the patientfeels on the tissue surface. This would correspond to a situation, forexample, in which at least 30%, preferably at least 50%, of the energystimulating the nerve comes from capacitive coupling through thestimulator interface, rather than from ohmic coupling. In other words, asubstantial portion (e.g., 50%) of the voltage drop is across thedielectric interface, while the remaining portion is through the tissue.

In certain exemplary embodiments, the interface and/or its underlyingmechanical support comprise materials that will also provide asubstantial or complete seal of the interior of the device. Thisinhibits any leakage of conducting material, such as gel, from theinterior of the device and also inhibits any fluids from entering thedevice. In addition, this feature allows the user to easily clean thesurface of the dielectric material (e.g., with isopropyl alcohol orsimilar disinfectant), avoiding potential contamination duringsubsequent uses of the device. One such material is a thin sheet ofMylar, supported by a stainless steel disc, as described above.

The selection of the material for the dielectric constant involves atleast two important variables: (1) the thickness of the interface; and(2) the dielectric constant of the material. The thinner the interfaceand/or the higher the dielectric constant of the material, the lower thevoltage drop across the dielectric interface (and thus the lower thedriving voltage required). For example, with Mylar, the thickness couldbe about 0.5 to 5 microns (preferably about 1 micron) with a dielectricconstant of about 3. For a piezoelectric material like barium titanateor PZT (lead zirconate titanate), the thickness could be about 100-400microns (preferably about 200 microns or 0.2 mm) because the dielectricconstant is >1000.

One of the novelties of the embodiment that is a non-invasive capacitivestimulator (hereinafter referred to more generally as a capacitiveelectrode) arises in that it uses a low voltage (generally less than 100volt) power source, which is made possible by the use of a suitablestimulation waveform, such as the waveform that is disclosed herein(FIG. 2). In addition, the capacitive electrode allows for the use of aninterface that provides a more adequate seal of the interior of thedevice. The capacitive electrode may be used by applying a small amountof conductive material (e.g., conductive gel as described above) to itsouter surface. In some embodiments, it may also be used by contactingdry skin, thereby avoiding the inconvenience of applying an electrodegel, paste, or other electrolytic material to the patient's skin andavoiding the problems associated with the drying of electrode pastes andgels. Such a dry electrode would be particularly suitable for use with apatient who exhibits dermatitis after the electrode gel is placed incontact with the skin [Ralph J. COSKEY. Contact dermatitis caused by ECGelectrode jelly. Arch Dermatol 113(1977): 839-840]. The capacitiveelectrode may also be used to contact skin that has been wetted (e.g.,with tap water or a more conventional electrolyte material) to make theelectrode-skin contact (here the dielectric constant) more uniform [A LALEXELONESCU, G Barbero, F C M Freire, and R Merletti. Effect ofcomposition on the dielectric properties of hydrogels for biomedicalapplications. Physiol. Meas. 31 (2010) S169-S182].

As described below, capacitive biomedical electrodes are known in theart, but when used to stimulate a nerve noninvasively, a high voltagepower supply is currently used to perform the stimulation. Otherwise,prior use of capacitive biomedical electrodes has been limited toinvasive, implanted applications; to non-invasive applications thatinvolve monitoring or recording of a signal, but not stimulation oftissue; to non-invasive applications that involve the stimulation ofsomething other than a nerve (e.g., tumor); or as the dispersiveelectrode in electrosurgery.

Evidence of a long-felt but unsolved need, and evidence of failure ofothers to solve the problem that is solved by the this embodiment of thepresent invention (low-voltage, non-invasive capacitive stimulation of anerve), is provided by KELLER and Kuhn, who review the previoushigh-voltage capacitive stimulating electrode of GEDDES et al and writethat “Capacitive stimulation would be a preferred way of activatingmuscle nerves and fibers, when the inherent danger of high voltagebreakdowns of the dielectric material can be eliminated. Goal of futureresearch could be the development of improved and ultra-thin dielectricfoils, such that the high stimulation voltage can be lowered.” [L. A.GEDDES, M. Hinds, and K. S. Foster. Stimulation with capacitorelectrodes. Medical and Biological Engineering and Computing 25(1987):359-360; Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous(surface) electrical stimulation. Journal of Automatic Control,University of Belgrade 18(2, 2008):35-45, on page 39]. It is understoodthat in the United States, according to the 2005 National ElectricalCode, high voltage is any voltage over 600 volts. U.S. Pat. No.3,077,884, entitled Electro-physiotherapy apparatus, to BARTROW et al,U.S. Pat. No. 4,144,893, entitled Neuromuscular therapy device, toHICKEY and U.S. Pat. No. 7,933,648, entitled High voltage transcutaneouselectrical stimulation device and method, to TANRISEVER, also describehigh voltage capacitive stimulation electrodes. U.S. Pat. No. 7,904,180,entitled Capacitive medical electrode, to JUOLA et al, describes acapacitive electrode that includes transcutaneous nerve stimulation asone intended application, but that patent does not describe stimulationvoltages or stimulation waveforms and frequencies that are to be usedfor the transcutaneous stimulation. U.S. Pat. No. 7,715,921, entitledElectrodes for applying an electric field in-vivo over an extendedperiod of time, to PALTI, and U.S. Pat. No. 7,805,201, entitled Treatinga tumor or the like with an electric field, to PALTI, also describecapacitive stimulation electrodes, but they are intended for thetreatment of tumors, do not disclose uses involving nerves, and teachstimulation frequencies in the range of 50 kHz to about 500 kHz.

This embodiment of the present invention uses a different method tolower the high stimulation voltage than developing ultra-thin dielectricfoils, namely, to use a suitable stimulation waveform, such as thewaveform that is disclosed herein (FIG. 2). That waveform hassignificant Fourier components at higher frequencies than waveforms usedfor transcutaneous nerve stimulation as currently practiced. Thus, oneof ordinary skill in the art would not have combined the claimedelements, because transcutaneous nerve stimulation is performed withwaveforms having significant Fourier components only at lowerfrequencies, and noninvasive capacitive nerve stimulation is performedat higher voltages. In fact, the elements in combination do not merelyperform the function that each element performs separately. Thedielectric material alone may be placed in contact with the skin inorder to perform pasteless or dry stimulation, with a more uniformcurrent density than is associated with ohmic stimulation, albeit withhigh stimulation voltages [L. A. GEDDES, M. Hinds, and K. S. Foster.Stimulation with capacitor electrodes. Medical and BiologicalEngineering and Computing 25(1987): 359-360; Yongmin K I M, H. GunterZieber, and Frank A. Yang. Uniformity of current density understimulating electrodes. Critical Reviews in Biomedical Engineering17(1990, 6): 585-619]. With regard to the waveform element, a waveformthat has significant Fourier components at higher frequencies thanwaveforms currently used for transcutaneous nerve stimulation may beused to selectively stimulate a deep nerve and avoid stimulating othernerves, as disclosed herein for both noncapacitive and capacitiveelectrodes. But it is the combination of the two elements (dielectricinterface and waveform) that makes it possible to stimulate a nervecapacitively without using the high stimulation voltage as is currentlypracticed.

Another embodiment of the electrode-based stimulator is shown in FIG. 5,showing a device in which electrically conducting material is dispensedfrom the device to the patient's skin. In this embodiment, the interface(351 in FIG. 2B) is the conducting material itself. FIGS. 5A and 5Brespectively provide top and bottom views of the outer surface of theelectrical stimulator 50. FIG. 5C provides a bottom view of thestimulator 50, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 5A and 5C show a mesh 51 with openings that permit a conductinggel to pass from inside of the stimulator to the surface of thepatient's skin at the position of nerve or tissue stimulation. Thus, themesh with openings 51 is the part of the stimulator that is applied tothe skin of the patient, through which conducting material may bedispensed. In any given stimulator, the distance between the two meshopenings 51 in FIG. 5A is constant, but it is understood that differentstimulators may be built with different inter-mesh distances, in orderto accommodate the anatomy and physiology of individual patients.Alternatively, the inter-mesh distance may be made variable as in theeyepieces of a pair of binoculars. A covering cap (not shown) is alsoprovided to fit snugly over the top of the stimulator housing and themesh openings 51, in order to keep the housing's conducting medium fromleaking or drying when the device is not in use.

FIGS. 5B and 5C show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and a power-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery power source (320 in FIG. 2B), and thepower-level controller is attached to the control unit (330 in FIG. 2B)of the device. The power source battery and power-level controller, aswell as the impulse generator (310 in FIG. 2B) are located (but notshown) in the rear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator (310 in FIG.2B) to the stimulator's electrodes 56. The two electrodes 56 are shownhere to be elliptical metal discs situated between the head compartment57 and rear compartment 55 of the stimulator 50. A partition 58separates each of the two head compartments 57 from one another and fromthe single rear compartment 55. Each partition 58 also holds itscorresponding electrode in place. However, each electrode 56 may beremoved to add electrically conducting gel (350 in FIG. 2B) to each headcompartment 57. An optional non-conducting variable-aperture irisdiaphragm may be placed in front of each of the electrodes within thehead compartment 57, in order to vary the effective surface area of eachof the electrodes. Each partition 58 may also slide towards the head ofthe device in order to dispense conducting gel through the meshapertures 51. The position of each partition 58 therefore determines thedistance 59 between its electrode 56 and mesh openings 51, which isvariable in order to obtain the optimally uniform current densitythrough the mesh openings 51. The outside housing of the stimulator 50,as well as each head compartment 57 housing and its partition 58, aremade of electrically insulating material, such as acrylonitrilebutadiene styrene, so that the two head compartments are electricallyinsulated from one another. Although the embodiment in FIG. 5 is shownto be a non-capacitive stimulator, it is understood that it may beconverted into a capacitive stimulator by replacing the mesh openings 51with a dielectric material, such as a sheet of Mylar, or by covering themesh openings 51 with a sheet of such dielectric material.

In preferred embodiments of the electrode-based stimulator shown in FIG.2B, electrodes are made of a metal, such as stainless steel, platinum,or a platinum-iridium alloy. However, in other embodiments, theelectrodes may have many other sizes and shapes, and they may be made ofother materials [Thierry KELLER and Andreas Kuhn. Electrodes fortranscutaneous (surface) electrical stimulation. Journal of AutomaticControl, University of Belgrade, 18(2, 2008):35-45; G. M. LYONS, G. E.Leane, M. Clarke-Moloney, J. V. O'Brien, P. A. Grace. An investigationof the effect of electrode size and electrode location on comfort duringstimulation of the gastrocnemius muscle. Medical Engineering & Physics26 (2004) 873-878; Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effectof Electrode Size, Shape, and Placement During Electrical Stimulation.The Journal of Applied Research 4, (2, 2004): 346-354; Gad ALON, GideonKantor and Henry S. Ho. Effects of Electrode Size on Basic ExcitatoryResponses and on Selected Stimulus Parameters. Journal of Orthopaedicand Sports Physical Therapy. 20(1, 1994):29-35].

For example, the stimulator's conducting materials may be nonmagnetic,and the stimulator may be connected to the impulse generator by longnonmagnetic wires (345 in FIG. 2B), so that the stimulator may be usedin the vicinity of a strong magnetic field, possibly with added magneticshielding. As another example, there may be more than two electrodes;the electrodes may comprise multiple concentric rings; and theelectrodes may be disc-shaped or have a non-planar geometry. They may bemade of other metals or resistive materials such as silicon-rubberimpregnated with carbon that have different conductive properties[Stuart F. COGAN. Neural Stimulation and Recording Electrodes. Annu.Rev. Biomed. Eng. 2008. 10:275-309; Michael F. NOLAN. Conductivedifferences in electrodes used with transcutaneous electrical nervestimulation devices. Physical Therapy 71(1991):746-751].

Although the electrode may consist of arrays of conducting material, theembodiments shown in FIGS. 4 and 5 avoid the complexity and expense ofarray or grid electrodes [Ana POPOVIC-BIJELIC, Goran Bijelic, NikolaJorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, and Dejan B.Popovic. Multi-Field Surface Electrode for Selective ElectricalStimulation. Artificial Organs 29 (6, 2005):448-452; Dejan B. POPOVICand Mirjana B. Popovic. Automatic determination of the optimal shape ofa surface electrode: Selective stimulation. Journal of NeuroscienceMethods 178 (2009) 174-181; Thierry KELLER, Marc Lawrence, Andreas Kuhn,and Manfred Morari. New Multi-Channel Transcutaneous ElectricalStimulation Technology for Rehabilitation. Proceedings of the 28th IEEEEMBS Annual International Conference New York City, USA, Aug. 30-Sep. 3,2006 (WeC14.5): 194-197]. This is because the designs shown in FIGS. 4and 5 provide a uniform surface current density, which would otherwisebe a potential advantage of electrode arrays, and which is a trait thatis not shared by most electrode designs [Kenneth R. BRENNEN. TheCharacterization of Transcutaneous Stimulating Electrodes. IEEETransactions on Biomedical Engineering BME-23 (4, 1976): 337-340; AndreiPATRICIU, Ken Yoshida, Johannes J. Struijk, Tim P. DeMonte, Michael L.G. Joy, and Hans Stødkilde-Jorgensen. Current Density Imaging andElectrically Induced Skin Burns Under Surface Electrodes. IEEETransactions on Biomedical Engineering 52 (12, 2005): 2024-2031; R. H.GEUZE. Two methods for homogeneous field defibrillation and stimulation.Med. and Biol. Eng. and Comput. 21(1983), 518-520; J. PETROFSKY, E.Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnsonand W. Remigo. Current distribution under electrodes in relation tostimulation current and skin blood flow: are modern electrodes reallyproviding the current distribution during stimulation we believe theyare? Journal of Medical Engineering and Technology 30 (6, 2006):368-381; Russell G. MAUS, Erin M. McDonald, and R. Mark Wightman.Imaging of Nonuniform Current Density at Microelectrodes byElectrogenerated Chemiluminescence. Anal. Chem. 71(1999): 4944-4950]. Infact, patients found the design shown in FIGS. 4 and 5 to be lesspainful in a direct comparison with a commercially availablegrid-pattern electrode [UltraStim grid-pattern electrode, AxelggardManufacturing Company, 520 Industrial Way, Fallbrook Calif., 2011]. Theembodiment of the electrode that uses capacitive coupling isparticularly suited to the generation of uniform stimulation currents[Yongmin K I M, H. Gunter Zieber, and Frank A. Yang. Uniformity ofcurrent density under stimulating electrodes. Critical Reviews inBiomedical Engineering 17(1990, 6): 585-619].

The electrode-based stimulator designs shown in FIGS. 4 and 5 situatethe electrode remotely from the surface of the skin within a chamber,with conducting material placed in the chamber between the skin andelectrode. Such a chamber design had been used prior to the availabilityof flexible, flat, disposable electrodes [U.S. Pat. No. 3,659,614,entitled Adjustable headband carrying electrodes for electricallystimulating the facial and mandibular nerves, to Jankelson; U.S. Pat.No. 3,590,810, entitled Biomedical body electode, to Kopecky; U.S. Pat.No. 3,279,468, entitled Electrotherapeutic facial mask apparatus, to LeVine; U.S. Pat. No. 6,757,556, entitled Electrode sensor, to Gopinathanet al; U.S. Pat. No. 4,383,529, entitled Iontophoretic electrode device,method and gel insert, to Webster; U.S. Pat. No. 4,220,159, entitledElectrode, to Francis et al. U.S. Pat. Nos. 3,862,633, 4,182,346, andU.S. Pat. No. 3,973,557, entitled Electrode, to Allison et al; U.S. Pat.No. 4,215,696, entitled Biomedical electrode with pressurized skincontact, to Bremer et al; and U.S. Pat. No. 4,166,457, entitled Fluidself-sealing bioelectrode, to Jacobsen et al.] The stimulator designsshown in FIGS. 4 and 5 are also self-contained units, housing theelectrodes, signal electronics, and power supply. Portable stimulatorsare also known in the art, for example, U.S. Pat. No. 7,171,266,entitled Electro-acupuncture device with stimulation electrode assembly,to Gruzdowich. One of the novelties of the designs shown in FIGS. 4 and5 is that the stimulator, along with a correspondingly suitablestimulation waveform, shapes the electric field, producing a selectivephysiological response by stimulating that nerve, but avoidingsubstantial stimulation of nerves and tissue other than the targetnerve, particularly avoiding the stimulation of nerves that producepain. The shaping of the electric field is described in terms of thecorresponding field equations in commonly assigned applicationUS20110230938 (application Ser. No. 13/075,746) entitled Devices andmethods for non-invasive electrical stimulation and their use for vagalnerve stimulation on the neck of a patient, to SIMON et al., which ishereby incorporated by reference.

In one embodiment, the magnetic stimulator coil 341 in FIG. 2A has abody that is similar to the electrode-based stimulator shown in FIG. 5C.To compare the electrode-based stimulator with the magnetic stimulator,refer to FIG. 5D, which shows the magnetic stimulator 530 sectionedalong its long axis to reveal its inner structure. As described below,it reduces the volume of conducting material that must surround atoroidal coil, by using two toroids, side-by-side, and passingelectrical current through the two toroidal coils in oppositedirections. In this configuration, the induced electrical current willflow from the lumen of one toroid, through the tissue and back throughthe lumen of the other, completing the circuit within the toroids'conducting medium. Thus, minimal space for the conducting medium isrequired around the outside of the toroids at positions near from thegap between the pair of coils. An additional advantage of using twotoroids in this configuration is that this design will greatly increasethe magnitude of the electric field gradient between them, which iscrucial for exciting long, straight axons such as the vagus nerve andcertain peripheral nerves.

As seen in FIG. 5D, a mesh 531 has openings that permit a conducting gel(within 351 in FIG. 2A) to pass from the inside of the stimulator to thesurface of the patient's skin at the location of nerve or tissuestimulation. Thus, the mesh with openings 531 is the part of themagnetic stimulator that is applied to the skin of the patient.

FIG. 5D also shows openings at the opposite end of the magneticstimulator 530. One of the openings is an electronics port 532 throughwhich wires pass from the stimulator coil(s) to the impulse generator(310 in FIG. 2A). The second opening is a conducting gel port 533through which conducting gel (351 in FIG. 2A) may be introduced into themagnetic stimulator 530 and through which a screw-driven piston arm maybe introduced to dispense conducting gel through the mesh 531. The gelitself is contained within cylindrical-shaped but interconnectedconducting medium chambers 534 that are shown in FIG. 5D. The depth ofthe conducting medium chambers 534, which is approximately the height ofthe long axis of the stimulator, affects the magnitude of the electricfields and currents that are induced by the magnetic stimulator device[Rafael CARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering. 48 (4, 2001): 434-441].

FIG. 5D also show the coils of wire 535 that are wound around toroidalcores 536, consisting of high-permeability material (e.g., Supermendur).Lead wires (not shown) for the coils 535 pass from the stimulatorcoil(s) to the impulse generator (310 in FIG. 2A) via the electronicsport 532. Different circuit configurations are contemplated. If separatelead wires for each of the coils 535 connect to the impulse generator(i.e., parallel connection), and if the pair of coils are wound with thesame handedness around the cores, then the design is for current to passin opposite directions through the two coils. On the other hand, if thecoils are wound with opposite handedness around the cores, then the leadwires for the coils may be connected in series to the impulse generator,or if they are connected to the impulse generator in parallel, then thedesign is for current to pass in the same direction through both coils.

As also seen in FIG. 5D, the coils 535 and cores 536 around which theyare wound are mounted as close as practical to the corresponding mesh531 with openings through which conducting gel passes to the surface ofthe patient's skin. As shown, each coil and the core around which it iswound is mounted in its own housing 537, the function of which is toprovide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium. A difference between thestructure of the electrode-based stimulator shown in FIG. 5C and themagnetic stimulator shown in FIG. 5D is that the conducting gel ismaintained within the chambers 57 of the electrode-based stimulator,which is generally closed on the back side of the chamber because of thepresence of the electrode 56; but in the magnetic stimulator, the holeof each toroidal core and winding is open, permitting the conducting gelto enter the interconnected chambers 534.

Application of the Stimulators to the Neck of the Patient

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retopharyngeal space oneach side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6 illustrates use of the devices shown in FIGS. 3, 4 and 5 tostimulate the vagus nerve at that location in the neck, in which thestimulator device 50 or 530 in FIG. 5 is shown to be applied to thetarget location on the patient's neck as described above. For reference,locations of the following vertebrae are also shown: first cervicalvertebra 71, the fifth cervical vertebra 75, the sixth cervical vertebra76, and the seventh cervical vertebra 77.

FIG. 7 provides a more detailed view of use of the electricalstimulator, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 6. As shown, the stimulator 50 inFIG. 5 touches the neck indirectly, by making electrical contact throughconducting gel 29 (or other conducting material) which may be isdispensed through mesh openings (identified as 51 in FIG. 5) of thestimulator or applied as an electrode gel or paste. The layer ofconducting gel 29 in FIG. 7 is shown to connect the device to thepatient's skin, but it is understood that the actual location of the gellayer(s) may be generally determined by the location of mesh 51 shown inFIG. 5. Furthermore, it is understood that for other embodiments of theinvention, the conductive head of the device may not necessitate the useof additional conductive material being applied to the skin.

The vagus nerve 60 is identified in FIG. 7, along with the carotidsheath 61 that is identified there in bold peripheral outline. Thecarotid sheath encloses not only the vagus nerve, but also the internaljugular vein 62 and the common carotid artery 63. Features that may beidentified near the surface of the neck include the external jugularvein 64 and the sternocleidomastoid muscle 65. Additional organs in thevicinity of the vagus nerve include the trachea 66, thyroid gland 67,esophagus 68, scalenus anterior muscle 69, and scalenus medius muscle70. The sixth cervical vertebra 76 is also shown in FIG. 7, with bonystructure indicated by hatching marks.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 6 and 7, using the electrical stimulation devicesthat are disclosed herein. Stimulation may be performed on the left orright vagus nerve or on both of them simulataneously or alternately. Theposition and angular orientation of the device are adjusted about thatlocation until the patient perceives stimulation when current is passedthrough the stimulator electrodes. The applied current is increasedgradually, first to a level wherein the patient feels sensation from thestimulation. The power is then increased, but is set to a level that isless than one at which the patient first indicates any discomfort.Straps, harnesses, or frames are used to maintain the stimulator inposition (not shown in FIG. 6). The stimulator signal may have afrequency and other parameters that are selected to produce atherapeutic result in the patient. Stimulation parameters for eachpatient are adjusted on an individualized basis. Ordinarily, theamplitude of the stimulation signal is set to the maximum that iscomfortable for the patient, and then the other stimulation parametersare adjusted.

The stimulation is then performed with a sinusoidal burst waveform likethat shown in FIG. 2. The pattern of a burst followed by silentinter-burst period repeats itself with a period of T. For example, thesinusoidal period t may be 200 microseconds; the number of pulses perburst may be N=5; and the whole pattern of burst followed by silentinter-burst period may have a period of T=40000 microseconds, which iscomparable to 25 Hz stimulation. More generally, there may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of 1 to 1000 microseconds (i.e., about 1 to 10 KHz),preferably 200 microseconds (about 5 KHz). A burst followed by a silentinter-burst interval repeats at 1 to 5000 bursts per second (bps),preferably at 5-50 bps, and even more preferably 10-25 bps stimulation(10-25 Hz). The preferred shape of each pulse is a full sinusoidal wave,although triangular or other shapes may be used as well. For mostpatients, the stimulation may be performed for 30 minutes and thetreatment is performed once a week for 12 weeks or longer, because theprogression of the disease from prodrome to true dementia is a chronicsituation. The stimulation may also be performed as the need arises,before the patient undertakes a cognitive challenge. It is understoodthat parameters of the stimulation protocol may be varied in response toheterogeneity in the pathophysiology and needs of patients.

In other embodiments of the invention, pairing of vagus nervestimulation may be with a additional sensory stimulation. The pairedsensory stimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect.

For example, the hypothalamus is well known to be responsive to thepresence of bright light, so exposing the patient to bright light thatis fluctuating with the same stimulation frequency as the vagus nerve(or a multiple of that frequency) may be performed in an attempt toenhance the role of the hypothalamus in producing the desiredtherapeutic effect. Flickering light induces frequency-locked EEGactivity that can resemble endogenous alpha waves and may even inducealpha-like activity, enhancing memory [WILLIAMS J, Ramaswamy D, OulhajA. 10 Hz flicker improves recognition memory in older people. BMCNeurosci 7(2006):21, pp. 1-7]. Such paired stimulation does notnecessarily rely upon neuronal plasticity and is in that sense differentfrom other reports of paired stimulation [Navzer D. ENGINEER, JonathanR. Riley, Jonathan D. Seale, Will A. Vrana, Jai A. Shetake, Sindhu P.Sudanagunta, Michael S. Borland and Michael P. Kilgard. Reversingpathological neural activity using targeted plasticity. Nature 470(7332,2011):101-104; PORTER B A, Khodaparast N, Fayyaz T, Cheung R J, Ahmed SS, Vrana W A, Rennaker R L 2nd, Kilgard M P. Repeatedly pairing vagusnerve stimulation with a movement reorganizes primary motor cortex.Cereb Cortex 22(10, 2012):2365-2374].

As noted above, the earliest stages of Alzheimer's disease areassociated with olfactory regions of the brain, and as the diseaseprogresses into mild cognitive impairment, the patient's sense of smellmay deteriorate [WILSON R S, Arnold S E, Schneider J A, Boyle P A,Buchman A S, Bennett D A. Olfactory impairment in presymptomaticAlzheimer's disease. Ann N Y Acad Sci 1170(2009):730-735]. Testing of apatient's sense of smell may be performed by presenting a standardodorant to the nose of the patient, with each odorant diluted in atypically eight log-step concentration series. The stimulusconcentrations are presented in an ascending series and sniffed fromstrips of blotter paper dipped into the odorant solutions. At a minimum,odor detection and recognition thresholds are measured for the patient[DOTY R L, Smith R, McKeown D A, Raj J. Tests of human olfactoryfunction: principal components analysis suggests that most measure acommon source of variance. Percept Psychophys 56(6, 1994): 701-707]. Ifthe tests are performed annually beginning in early adulthood, thepatient may at some point exibit a deteriorating sense of smell, asevidenced by increased odor detection thresholds. At that point, orearlier if the patient has a family history of Alzheimer's disease, thepresent invention may be used in an effort to enhance or at leastmaintain the olfactory regions of the patient's brain, thereby servingas a prophylactic or treatment for AD. The disclosed method involvesvagus nerve stimulation paired with the presentation of an odorant, ator above the measured odor detection threshold. The paired stimulationmay be performed for 30 minutes and the treatment is performed onceevery two weeks for 12 weeks or longer. If after successive treatmentsthe patient's sense of smell improves for an odorant, the process may berepeated with other odorants. One rationale for this method is that themammalian main olfactory bulb receives a significant noradrenergic inputfrom the locus ceruleus [LINSTER C, Nai Q, Ennis M. Nonlinear effects ofnoradrenergic modulation of olfactory bulb function in adult rodents. JNeurophysiol. 2011 April; 105(4, 2011):1432-1443].

Selection of stimulation parameters to preferentially stimulateparticular regions of the brain may be done empirically, wherein a setof stimulation parameters are chosen, and the responsive region of thebrain is measured using fMRI or a related imaging method [CHAE J H,Nahas Z, Lomarev M, Denslow S, Lorberbaum J P, Bohning D E, George M S.A review of functional neuroimaging studies of vagus nerve stimulation(VNS). J Psychiatr Res. 37(6, 2003):443-455; CONWAY C R, Sheline Y I,Chibnall J T, George M S, Fletcher J W, Mintun M A. Cerebral blood flowchanges during vagus nerve stimulation for depression. Psychiatry Res.146(2, 2006):179-84]. Thus, by performing the imaging with differentsets of stimulation parameters, a database may be constructed, such thatthe inverse problem of selecting parameters to match a particular brainregion may be solved by consulting the database.

Stimulation waveforms may also be constructed by superimposing or mixingthe burst waveform shown in FIG. 2, in which each component of themixture may have a different period T, effectively mixing differentburst-per-second waveforms. The relative amplitude of each component ofthe mixture may be chosen to have a weight according to correlations indifferent bands in an EEG for a particular resting state network. Thus,MANTINI et al performed simultaneous fMRI and EEG measurements and foundthat each resting state network has a particular EEG signature [see FIG.3 in: MANTINI D, Perrucci M G, Del Gratta C, Romani G L, Corbetta M.Electrophysiological signatures of resting state networks in the humanbrain. Proc Natl Acad Sci USA 104(32, 2007):13170-13175]. They reportedrelative correlations in each of the following bands, for each restingstate network that was measured: delta (1-4 Hz), theta (4-8 Hz), alpha(8-13 Hz), beta (13-30 Hz), and gamma (30-50 Hz) rhythms.

According to the present embodiment of the invention, multiple signalsshown in FIG. 2 are constructed, with periods T that correspond to alocation near the midpoint of each of the EEG bands (T equalsapproximately 0.4 sec, 0.1667 sec, 0.095 sec, 0.0465 sec, and 0.025 sec,respectively). A more comprehensive mixture could also be made by mixingmore than one signal for each band. These signals are then mixed, withrelative amplitudes corresponding to the weights measured for anyparticular resting state network, and the mixture is used to stimulatethe vagus nerve of the patient. Phases between the mixed signals areadjusted to optimize the fMRI signal for the resting state network thatis being stimulated. Stimulation of a network may activate or deactivatea network, depending on the detailed configuration of adrenergicreceptors within the network and their roles in enhancing or depressingneural activity within the network, as well as subsequentnetwork-to-network interactions. It is understood that variations ofthis method may be used when different combined fMRI-EEG procedures areemployed and where the same resting state may have different EEGsignatures, depending on the circumstances [WU C W, Gu H, Lu H, Stein EA, Chen J H, Yang Y. Frequency specificity of functional connectivity inbrain networks. Neuroimage 42(3, 2008):1047-1055; LAUFS H. Endogenousbrain oscillations and related networks detected by surface EEG-combinedfMRI. Hum Brain Mapp 29(7, 2008):762-769; MUSSO F, Brinkmeyer J,Mobascher A, Warbrick T, Winterer G. Spontaneous brain activity and EEGmicrostates. A novel EEG/fMRI analysis approach to explore resting-statenetworks. Neuroimage 52(4, 2010):1149-1161; ESPOSITO F, Aragri A,Piccoli T, Tedeschi G, Goebel R, Di Salle F. Distributed analysis ofsimultaneous EEG-fMRI time-series: modeling and interpretation issues.Magn Reson Imaging 27(8, 2009):1120-1130; FREYER F, Becker R, Anami K,Curio G, Villringer A, Ritter P. Ultrahigh-frequency EEG during fMRI:pushing the limits of imaging-artifact correction. Neuroimage 48(1,2009):94-108].

The individualized selection of parameters for the nerve stimulationprotocol may based on trial and error in order to obtain a beneficialresponse without the sensation of pain or muscle twitches. Ordinarily,the amplitude of the stimulation signal is set to the maximum that iscomfortable for the patient, and then the other stimulation parametersare adjusted. Alternatively, the selection of parameter values mayinvolve tuning as understood in control theory, and as described below.It is understood that parameters may also be varied randomly in order tosimulate normal physiological variability, thereby possibly inducing abeneficial response in the patient [Buchman T G. Nonlinear dynamics,complex systems, and the pathobiology of critical illness. Curr OpinCrit Care 10(5, 2004):378-82].

Use of Control Theory Methods to Improve Treatment of IndividualPatients

The vagus nerve stimulation may employ methods of control theory (e.g.,feedback) in an attempt to compensate for motion of the stimulatorrelative to the vagus nerve; to avoid potentially dangerous situationssuch as excessive heart rate; and to maintain measured EEG bands (e.g.,delta, theta, alpha, beta) within predetermined ranges, in attempt topreferentially activate particular resting state networks. Thus, withthese methods, the parameters of the vagus nerve stimulation may bechanged automatically, depending on physiological measurements that aremade, in attempt to maintain the values of the physiological signalswithin predetermined ranges.

The effects of vagus nerve stimulation on surface EEG waveforms may bedifficult to detect [Michael BEWERNITZ, Georges Ghacibeh, Onur Seref,Panos M. Pardalos, Chang-Chia Liu, and Basim Uthman. Quantification ofthe impact of vagus nerve stimulation parameters onelectroencephalographic measures. AIP Conf. Proc. DATA MINING, SYSTEMSANALYSIS AND OPTIMIZATION IN BIOMEDICINE; Nov. 5, 2007, Volume 953, pp.206-219], but they may exist nevertheless [KOO B. EEG changes with vagusnerve stimulation. J Clin Neurophysiol. 18(5, 2001):434-41; KUBA R,Guzaninová M, Brázdil M, Novák Z, Chrastina J, Rektor I. Effect of vagalnerve stimulation on interictal epileptiform discharges: a scalp EEGstudy. Epilepsia. 43(10, 2002):1181-8; RIZZO P, Beelke M, De Carli F,Canovaro P, Nobili L, Robert A, Fornaro P, Tanganelli P, Regesta G,Ferrillo F. Modifications of sleep EEG induced by chronic vagus nervestimulation in patients affected by refractory epilepsy. ClinNeurophysiol. 115(3, 2004):658-64].

When stimulating the vagus nerve, motion variability is most oftenattributable to the patient's breathing, which involves contraction andassociated change in geometry of the sternocleidomastoid muscle that issituated close to the vagus nerve (identified as 65 in FIG. 7).Modulation of the stimulator amplitude to compensate for thisvariability may be accomplished by measuring the patient's respiratoryphase, or more directly by measuring movement of the stimulator, thenusing controllers (e.g., PID controllers) that are known in the art ofcontrol theory, as now described.

FIG. 8 is a control theory representation of the disclosed vagus nervestimulation methods. As shown there, the patient, or the relevantphysiological component of the patient, is considered to be the “System”that is to be controlled. The “System” (patient) receives input from the“Environment.” For example, the environment would include ambienttemperature, light, and sound. If the “System” is defined to be only aparticular physiological component of the patient, the “Environment” mayalso be considered to include physiological systems of the patient thatare not included in the “System”. Thus, if some physiological componentcan influence the behavior of another physiological component of thepatient, but not vice versa, the former component could be part of theenvironment and the latter could be part of the system. On the otherhand, if it is intended to control the former component to influence thelatter component, then both components should be considered part of the“System.”

The System also receives input from the “Controller”, which in this casemay comprise the vagus nerve stimulation device, as well as electroniccomponents that may be used to select or set parameters for thestimulation protocol (amplitude, frequency, pulse width, burst number,etc.) or alert the patient as to the need to use or adjust thestimulator (i.e., an alarm). For example, the controller may include thecontrol unit 330 in FIG. 2. Feedback in the schema shown in FIG. 8 ispossible because physiological measurements of the System are made usingsensors. Thus, the values of variables of the system that could bemeasured define the system's state (“the System Output”). As a practicalmatter, only some of those measurements are actually made, and theyrepresent the “Sensed Physiological Input” to the Controller.

The preferred sensors will include ones ordinarily used for ambulatorymonitoring. For example, the sensors may comprise those used inconventional Holter and bedside monitoring applications, for monitoringheart rate and variability, ECG, respiration depth and rate, coretemperature, hydration, blood pressure, brain function, oxygenation,skin impedance, and skin temperature. The sensors may be embedded ingarments or placed in sports wristwatches, as currently used in programsthat monitor the physiological status of soldiers [G. A. SHAW, A. M.Siegel, G. Zogbi, and T. P. Opar. Warfighter physiological andenvironmental monitoring: a study for the U.S. Army Research Institutein Environmental Medicine and the Soldier Systems Center. MIT LincolnLaboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141]. The ECG sensorsshould be adapted to the automatic extraction and analysis of particularfeatures of the ECG, for example, indices of P-wave morphology, as wellas heart rate variability indices of parasympathetic and sympathetictone. Measurement of respiration using noninvasive inductiveplethysmography, mercury in silastic strain gauges or impedancepneumography is particularly advised, in order to account for theeffects of respiration on the heart. A noninvasive accelerometer mayalso be included among the ambulatory sensors, in order to identifymotion artifacts. An event marker may also be included in order for thepatient to mark relevant circumstances and sensations.

For brain monitoring, the sensors may comprise ambulatory EEG sensors[CASSON A, Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3, 2010):44-56] or optical topographysystems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 April; 80(4):043704]. Signal processing methods,comprising not only the application of conventional linear filters tothe raw EEG data, but also the nearly real-time extraction of non-linearsignal features from the data, may be considered to be a part of the EEGmonitoring [D. Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U,and Choo Min Lim. EEG signal analysis: A survey. J Med Syst34(2010):195-212]. In the present application, the features wouldinclude EEG bands (e.g., delta, theta, alpha, beta).

Detection of the phase of respiration may be performed non-invasively byadhering a thermistor or thermocouple probe to the patient's cheek so asto position the probe at the nasal orifice. Strain gauge signals frombelts strapped around the chest, as well as inductive plethysmographyand impedance pneumography, are also used traditionally tonon-invasively generate a signal that rises and falls as a function ofthe phase of respiration. After digitizing such signals, the phase ofrespiration may be determined using software such as “puka”, which ispart of PhysioToolkit, a large published library of open source softwareand user manuals that are used to process and display a wide range ofphysiological signals [GOLDBERGER A L, Amaral L A N, Glass L, HausdorffJ M, Ivanov P Ch, Mark R G, Mietus J E, Moody G B, Peng C K, Stanley HE. PhysioBank, PhysioToolkit, and PhysioNet: Components of a NewResearch Resource for Complex Physiologic Signals. Circulation 101(23,2000):e215-e220] available from PhysioNet, M.I.T. Room E25-505A, 77Massachusetts Avenue, Cambridge, Mass. 02139]. In one embodiment of thepresent invention, the control unit 330 contains an analog-to-digitalconverter to receive such analog respiratory signals, and software forthe analysis of the digitized respiratory waveform resides within thecontrol unit 330. That software extracts turning points within therespiratory waveform, such as end-expiration and end-inspiration, andforecasts future turning-points, based upon the frequency with whichwaveforms from previous breaths match a partial waveform for the currentbreath. The control unit 330 then controls the impulse generator 310,for example, to stimulate the selected nerve only during a selectedphase of respiration, such as all of inspiration or only the firstsecond of inspiration, or only the expected middle half of inspiration.

It may be therapeutically advantageous to program the control unit 330to control the impulse generator 310 in such a way as to temporallymodulate stimulation by the magnetic stimulator coils or electrodes,depending on the phase of the patient's respiration. In patentapplication JP2008/081479A, entitled Vagus nerve stimulation system, toYOSHIHOTO, a system is also described for keeping the heart rate withinsafe limits. When the heart rate is too high, that system stimulates apatient's vagus nerve, and when the heart rate is too low, that systemtries to achieve stabilization of the heart rate by stimulating theheart itself, rather than use different parameters to stimulate thevagus nerve. In that disclosure, vagal stimulation uses an electrode,which is described as either a surface electrode applied to the bodysurface or an electrode introduced to the vicinity of the vagus nervevia a hypodermic needle. That disclosure is unrelated to the problem ofdementia that is addressed here, but it does consider stimulation duringparticular phases of the respiratory cycle, for the following reason.Because the vagus nerve is near the phrenic nerve, Yoshihoto indicatesthat the phrenic nerve will sometimes be electrically stimulated alongwith the vagus nerve. The present applicants have not experienced thisproblem, so the problem may be one of a misplaced electrode. In anycase, the phrenic nerve controls muscular movement of the diaphragm, soconsequently, stimulation of the phrenic nerve causes the patient tohiccup or experience irregular movement of the diaphragm, or otherwiseexperience discomfort. To minimize the effects of irregular diaphragmmovement, Yoshihoto's system is designed to stimulate the phrenic nerve(and possibly co-stimulate the vagus nerve) only during the inspirationphase of the respiratory cycle and not during expiration. Furthermore,the system is designed to gradually increase and then decrease themagnitude of the electrical stimulation during inspiration (notablyamplitude and stimulus rate) so as to make stimulation of the phrenicnerve and diaphragm gradual.

Patent application publication US2009/0177252, entitled Synchronizationof vagus nerve stimulation with the cardiac cycle of a patient, toArthur D. Craig, discloses a method of treating a medical condition inwhich the vagus nerve is stimulated during a portion of the cardiaccycle and the respiratory cycle. That disclosure pertains to thetreatment of a generic medical condition, so it is not specificallydirected to the treatment of dementia.

In some embodiments of the invention, overheating of the magneticstimulator coil may also be minimized by optionally restricting themagnetic stimulation to particular phases of the respiratory cycle,allowing the coil to cool during the other phases of the respiratorycycle. Alternatively, greater peak power may be achieved per respiratorycycle by concentrating all the energy of the magnetic pulses intoselected phases of the respiratory cycle.

Furthermore, as an option in the present invention, parameters of thestimulation may be modulated by the control unit 330 to control theimpulse generator 310 in such a way as to temporally modulatestimulation by the magnetic stimulator coil or electrodes, so as toachieve and maintain the heart rate within safe or desired limits. Inthat case, the parameters of the stimulation are individually raised orlowered in increments (power, frequency, etc.), and the effect as anincreased, unchanged, or decreased heart rate is stored in the memory ofthe control unit 330. When the heart rate changes to a value outside thespecified range, the control unit 330 automatically resets theparameters to values that had been recorded to produce a heart ratewithin that range, or if no heart rate within that range has yet beenachieved, it increases or decreases parameter values in the directionthat previously acquired data indicate would change the heart rate inthe direction towards a heart rate in the desired range. Similarly, thearterial blood pressure is also recorded non-invasively in an embodimentof the invention, and as described above, the control unit 330 extractsthe systolic, diastolic, and mean arterial blood pressure from the bloodpressure waveform. The control unit 330 will then control the impulsegenerator 310 in such a way as to temporally modulate nerve stimulationby the magnetic stimulator coil or electrodes, in such a way as toachieve and maintain the blood pressure within predetermined safe ordesired limits, by the same method that was indicated above for theheart rate. Thus, even if one does not intend to treat dementia,embodiments of the invention described above may be used to achieve andmaintain the heart rate and blood pressure within desired ranges.

Let the measured output variables of the system in FIG. 8 be denoted byy_(i) (i=1 to Q); let the desired (reference or setpoint) values ofy_(i) be denoted by r_(i) and let the controller's input to the systemconsist of variables u_(j) (j=1 to P). The objective is for a controllerto select the input u_(j) in such a way that the output variables (or asubset of them) closely follows the reference signals r_(i), i.e., thecontrol error e_(i)=r_(i)−y_(i) is small, even if there is environmentalinput or noise to the system. Consider the error functione_(i)=r_(i)−y_(i) to be the sensed physiological input to the controllerin FIG. 8 (i.e., the reference signals are integral to the controller,which subtracts the measured system values from them to construct thecontrol error signal). The controller will also receive a set ofmeasured environmental signals v_(k) (k=1 to R), which also act upon thesystem as shown in FIG. 8.

The functional form of the system's input u(t) is constrained to be asshown in FIGS. 2D and 2E. Ordinarily, a parameter that needs adjustingis the one associated with the amplitude of the signal shown in FIG. 2.As a first example of the use of feedback to control the system,consider the problem of adjusting the input u(t) from the vagus nervestimulator (i.e., output from the controller) in order to compensate formotion artifacts.

Nerve activation is generally a function of the second spatialderivative of the extracellular potential along the nerve's axon, whichwould be changing as the position of the stimulator varies relative tothe axon [F. RATTAY. The basic mechanism for the electrical stimulationof the nervous system. Neuroscience 89 (2, 1999):335-346]. Such motionartifact can be due to movement by the patient (e.g., neck movement) ormovement within the patient (e.g. sternocleidomastoid muscle contractionassociated with respiration), or it can be due to movement of thestimulator relative to the body (slippage or drift). Thus, one expectsthat because of such undesired or unavoidable motion, there will usuallybe some error (e=r−y) in the intended (r) versus actual (y) nervestimulation amplitude that needs continuous adjustment.

Accelerometers can be used to detect all these types of movement, usingfor example, Model LSM330DL from STMicroelectronics, 750 Canyon Dr #300Coppell, TX 75019. One or more accelerometer is attached to thepatient's neck, and one or more accelerometer is attached to the head ofthe stimulator in the vicinity of where the stimulator contacts thepatient. Because the temporally integrated outputs of the accelerometersprovide a measurement of the current position of each accelerometer, thecombined accelerometer outputs make it possible to measure any movementof the stimulator relative to the underlying tissue.

The location of the vagus nerve underlying the stimulator may bedetermined preliminarily by placing an ultrasound probe at the locationwhere the center of the stimulator will be placed [KNAPPERTZ V A,Tegeler C H, Hardin S J, McKinney W M. Vagus nerve imaging withultrasound: anatomic and in vivo validation. Otolaryngol Head Neck Surg118(1, 1998):82-5]. The ultrasound probe is configured to have the sameshape as the stimulator, including the attachment of one or moreaccelerometer. As part of the preliminary protocol, the patient withaccelerometers attached is then instructed to perform neck movements,breathe deeply so as to contract the sternocleidomastoid muscle, andgenerally simulate possible motion that may accompany prolongedstimulation with the stimulator. This would include possible slippage ormovement of the stimulator relative to an initial position on thepatient's neck. While these movements are being performed, theaccelerometers are acquiring position information, and the correspondinglocation of the vagus nerve is determined from the ultrasound image.With these preliminary data, it is then possible to infer the locationof the vagus nerve relative to the stimulator, given only theaccelerometer data during a stimulation session, by interpolatingbetween the previously acquired vagus nerve position data as a functionof accelerometer position data.

For any given position of the stimulator relative to the vagus nerve, itis also possible to infer the amplitude of the electric field that itproduces in the vicinity of the vagus nerve. This is done by calculationor by measuring the electric field that is produced by the stimulator asa function of depth and position within a phantom that simulates therelevant bodily tissue [Francis Marion MOORE. Electrical Stimulation forpain suppression: mathematical and physical models. Thesis, School ofEngineering, Cornell University, 2007; Bartosz SAWICKI, Robert Szmurło,Przemysław Płonecki, Jacek Starzyński, Stanisław Wincenciak, AndrzejRysz. Mathematical Modelling of Vagus Nerve Stimulation. pp. 92-97 in:Krawczyk, A. Electromagnetic Field, Health and Environment: Proceedingsof EHE′07. Amsterdam, IOS Press, 2008]. Thus, in order to compensate formovement, the controller may increase or decrease the amplitude of theoutput from the stimulator (u) in proportion to the inferred deviationof the amplitude of the electric field in the vicinity of the vagusnerve, relative to its desired value.

For present purposes, no distinction is made between a system outputvariable and a variable representing the state of the system. Then, astate-space representation, or model, of the system consists of a set offirst order differential equations of the form dy_(i)/dt=F_(i)(t,{y_(i)}, {u_(j)}, {v_(k)}; {r_(i)}), where t is timeand where in general, the rate of change of each variable y_(i) is afunction (F_(i)) of many other output variables as well as the input andenvironmental signals.

Classical control theory is concerned with situations in which thefunctional form of F, is as a linear combination of the state and inputvariables, but in which coefficients of the linear terms are notnecessarily known in advance. In this linear case, the differentialequations may be solved with linear transform (e.g., Laplace transform)methods, which convert the differential equations into algebraicequations for straightforward solution. Thus, for example, asingle-input single-output system (dropping the subscripts on variables)may have input from a controller of the form:

${u(t)} = {{K_{p}{e(t)}} + {K_{i}{\int_{0}^{t}{{e(\tau)}d\; \tau}}} + {K_{d}\frac{ds}{dt}}}$

where the parameters for the controller are the proportional gain(K_(p)), the integral gain (K_(i)) and the derivative gain (K_(d)). Thistype of controller, which forms a controlling input signal with feedbackusing the error e=r−y, is known as a PID controller(proportional-integral-derivative).

Optimal selection of the parameters of the controller could be throughcalculation, if the coefficients of the corresponding state differentialequation were known in advance. However, they are ordinarily not known,so selection of the controller parameters (tuning) is accomplished byexperiments in which the error e either is or is not used to form thesystem input (respectively, closed loop or open loop experiments). In anopen loop experiment, the input is increased in a step (or random binarysequence of steps), and the system response is measured. In a closedloop experiment, the integral and derivative gains are set to zero, theproportional gain is increased until the system starts to oscillate, andthe period of oscillation is measured. Depending on whether theexperiment is open or closed loop, the selection of PID parameter valuesmay then be selected according to rules that were described initially byZiegler and Nichols. There are also many improved versions of tuningrules, including some that can be implemented automatically by thecontroller [LI, Y., Ang, K. H. and Chong, G. C. Y. Patents, software andhardware for PID control: an overview and analysis of the current art.IEEE Control Systems Magazine, 26 (1, 2006): 42-54; Karl Johan Åstróm &Richard M. Murray. Feedback Systems: An Introduction for Scientists andEngineers. Princeton N.J.: Princeton University Press, 2008; FinnHAUGEN. Tuning of PID controllers (Chapter 10) In: Basic Dynamics andControl. 2009. ISBN 978-82-91748-13-9. TechTeach, Enggravhøgda 45,N-3711 Skien, Norway. http://techteach.no., pp. 129-155; Dingyu X U E,YangQuan Chen, Derek P. Atherton. PID controller design (Chapter 6), In:Linear Feedback Control: Analysis and Design with MATLAB. Society forIndustrial and Applied Mathematics (SIAM). 3600 Market Street, 6thFloor, Philadelphia, Pa. (2007), pp. 183-235; Jan JANTZEN, Tuning OfFuzzy PID Controllers, Technical University of Denmark, report 98-H 871,Sep. 30, 1998].

Commercial versions of PID controllers are available, and they are usedin 90% of all control applications. To use such a controller, forexample, in an attempt to maintain the EEG gamma band at a particularlevel relative to the alpha band, one could set the integral andderivative gains to zero, increase the proportional gain (amplitude ofthe stimulation) until the relative gamma band level starts tooscillate, and then measure the period of oscillation. The PID wouldthen be set to its tuned parameter values.

Although classical control theory works well for linear systems havingone or only a few system variables, special methods have been developedfor systems in which the system is nonlinear (i.e., the state-spacerepresentation contains nonlinear differential equations), or multipleinput/output variables. Such methods are important for the presentinvention because the physiological system to be controlled will begenerally nonlinear, and there will generally be multiple outputphysiological signals. It is understood that those methods may also beimplemented in the controller shown in FIG. 8 [Torkel GLAD and LennartLjung. Control Theory. Multivariable and Nonlinear Methods. New York:Taylor and Francis, 2000; Zdzislaw BUBNICKI. Modern Control Theory.Berlin: Springer, 2005].

The controller shown in FIG. 8 may also make use of feed-forward methods[Coleman BROSILOW, Babu Joseph. Feedforward Control (Chapter 9) In:Techniques of Model-Based Control. Upper Saddle River, N.J.: PrenticeHall PTR, 2002. pp, 221-240]. Thus, the controller in FIG. 8 may be atype of predictive controller, methods for which have been developed inother contexts as well, such as when a model of the system is used tocalculate future outputs of the system, with the objective of choosingamong possible inputs so as to optimize a criterion that is based onfuture values of the system's output variables.

Performance of system control can be improved by combining the feedbackclosed-loop control of a PID controller with feed-forward control,wherein knowledge about the system's future behavior can be fed forwardand combined with the PID output to improve the overall systemperformance. For example, if the sensed environmental input in FIG. 8 issuch the environmental input to the system will have a deleteriouseffect on the system after a delay, the controller may use thisinformation to provide anticipatory control input to the system, so asto avert or mitigate the deleterious effects that would have been sensedonly after-the-fact with a feedback-only controller.

A mathematical model of the system is needed in order to perform thepredictions of system behavior, e.g., make predictions concerning theonset of a cognitive fluctuation in a dementia patient. Models that arecompletely based upon physical first principles (white-box) are rare,especially in the case of physiological systems. Instead, most modelsthat make use of prior structural and mechanistic understanding of thesystem are so-called grey-box models. If the mechanisms of the systemsare not sufficiently understood in order to construct a white or greybox model, a black-box model may be used instead. Such black box modelscomprise autoregressive models [Tim BOLLERSLEV. Generalizedautoregressive condiditional heteroskedasticity. Journal of Econometrics31(1986):307-327], or those that make use of principal components [JamesH. STOCK, Mark W. Watson. Forecasting with Many Predictors, In: Handbookof Economic Forecasting. Volume 1, G. Elliott, C. W. J. Granger and A.Timmermann, eds (2006) Amsterdam: Elsevier B. V, pp 515-554], Kalmanfilters [Eric A. WAN and Rudolph van der Merwe. The unscented Kalmanfilter for nonlinear estimation, In: Proceedings of Symposium 2000 onAdaptive Systems for Signal Processing, Communication and Control(AS-SPCC), IEEE, Lake Louise, Alberta, Canada, October, 2000, pp153-158], wavelet transforms [O. RENAUD, J.-L. Stark, F. Murtagh.Wavelet-based forecasting of short and long memory time series. SignalProcessing 48(1996):51-65], hidden Markov models [Sam ROWEIS and ZoubinGhahramani. A Unifying Review of Linear Gaussian Models. NeuralComputation 11(2, 1999): 305-345], or artificial neural networks[Guoquiang ZHANG, B. Eddy Patuwo, Michael Y. Hu. Forecasting withartificial neural networks: the state of the art. International Journalof Forecasting 14(1998): 35-62].

For the present invention, if a black-box model must be used, thepreferred model will be one that makes use of support vector machines. Asupport vector machine (SVM) is an algorithmic approach to the problemof classification within the larger context of supervised learning. Anumber of classification problems whose solutions in the past have beensolved by multi-layer back-propagation neural networks, or morecomplicated methods, have been found to be more easily solvable by SVMs[Christopher J. C. BURGES. A tutorial on support vector machines forpattern recognition. Data Mining and Knowledge Discovery 2(1998),121-167; J. A. K. SUYKENS, J. Vandewalle, B. De Moor. Optimal Control byLeast Squares Support Vector Machines. Neural Networks 14 (2001):23-35;SAPANKEVYCH, N. and Sankar, R. Time Series Prediction Using SupportVector Machines: A Survey. IEEE Computational Intelligence Magazine 4(2,2009): 24-38; PRESS, W H; Teukolsky, S A; Vetterling, W T; Flannery, B P(2007). Section 16.5. Support Vector Machines. In: Numerical Recipes:The Art of Scientific Computing (3rd ed.). New York: CambridgeUniversity Press].

In this example, a training set of physiological data will have beenacquired that includes whether or not the patient is experiencing acognitive fluctuation. Thus, the classification of the patient's stateis whether or not the fluctuation is in progress, and the data used tomake the classification consist of the acquired physiological data: EEGand its derived features; respiration (abdominal and thoracicplethysmography), carbon dioxide (capnometry with nasual cannula), heartrate (electrocardiogram leads), skin impedance (electrodermal leads),vocalization (microphones), light (light sensor), motion(accelerometer), external and finger temperature (thermometers), etc.,as well as parameters of the stimulator device (if it is currently beingused on a patient experiencing a fluctuation), evaluated at D time unitsprior to the time at which binary “in fluctuation” (yes/no) data areacquired, as indicated by the patient or a caregiver. Thus, for apatient who is experiencing a fluctuation, the SVM is trained toforecast the termination of fluctuation, Δ time units into the future,and the training set includes the time-course of features extracted fromthe above-mentioned physiological signals. For a patient who is notexperiencing a cognitive fluctuation, the SVM is trained to forecast theimminence of a fluctuation, Δ time units into the future, and thetraining set includes the above-mentioned physiological signals. Aftertraining the SVM, it is implemented as part of the controller. Forpatients who are not experiencing a fluctuation, the controller maysound an alarm and advise the use of vagal nerve stimulation, wheneverthere is a forecast of an imminent cognitive fluctuation.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A device for treating or preventing dementia in a patient comprising:a housing having an interior portion and an exterior portion; anelectrically permeable contact surface formed on at least part of theexterior portion of the housing and configured for contacting an outerskin surface of a neck of the patient; one or more electrodeselectrically coupled to the electrically permeable contact surface; apower source within the interior portion of the housing and configuredto generate an electric field sufficient to transmit an electric currentnon-invasively and transcutaneously via the one or more electrodesthrough the electrically permeable contact surface and the outer skinsurface of the neck of the patient to a vagus nerve within the patient;and wherein the electric current is sufficient to modify dementia in thepatient.
 2. The device of claim 1 wherein the energy source comprises asignal generator.
 3. The device of claim 1 wherein the energy sourcecomprises a battery.
 4. The device of claim 1 further comprising avolume of electrically conductive fluid within the interior portion ofthe housing and at least partially surrounding the one or moreelectrodes.
 5. The device of claim 1 wherein the electric currentcomprises bursts of pulses and with each of the bursts followed by asilent intra-burst period.
 6. The device of claim 5 wherein the burstshave a frequency of about 1 to about 100 bursts per second.
 7. Thedevice of claim 6 wherein the frequency is about 5 to 50 Hz.
 8. Thedevice of claim 5 wherein the electric current comprises about 2 to 50pulses per burst with each pulse having a duration of about 50 to 1000microseconds.
 9. The device of claim 8 wherein the duration of thepulses is about 200 to 400 microseconds.
 10. The device of claim 1wherein the electric current is sufficient to modulate the vagus nerveand cause the vagus nerve to generate an action potential.
 11. Thedevice of claim 1 wherein the housing is a handheld device.
 12. Thedevice of claim 1 wherein the electric current generates an electricfield at the vagus nerve above a threshold for generating actionpotentials within A and B fibers of the vagus nerve and below athreshold for generating action potentials within C fibers of the vagusnerve.
 13. The device of claim 1 wherein the electric current generatesan electric field at the vagus nerve of about 10 to about 600 V/m. 14.The device of claim 13 wherein the electric field is less than 100 V/m.15. The device of claim 1 wherein the electric current generates anelectric field at the vagus nerve above a threshold for generatingaction potentials within fibers of the vagus nerve responsible foractivating neural pathways causing release of inhibitoryneurotransmitters within a brain of the patient.
 16. The device of claim15 wherein the inhibitory neurotransmitters comprise norepinephrine. 17.A device for treating or preventing dementia in a patient comprising: ahousing comprising an exterior portion having one or more electrodes forcontacting an outer skin surface of a neck of the patient; an energysource within the housing configured to generate an electric current andtransmit the electric current transcutaneously and non-invasivelythrough the outer skin surface of the neck of the patient to a vagusnerve within the patient; and wherein the electric current is suffientto treat or prevent dementia in the patient.
 18. The device of claim 17wherein the energy source comprises a battery and a signal generator,wherein the one or more electrodes are coupled to the signal generatorwithin the housing.
 19. The device of claim 17 wherein the electriccurrent comprises bursts of pulses with each of the bursts followed by asilent intra-burst period such that the bursts have a frequency of about1 to about 100 Hz.
 20. The device of claim 19 wherein the electriccurrent comprises about 2 to 50 pulses per burst, with each pulse have aduration of about 50 to about 1000 microseconds.